Quinuclidine compounds as alpha-7 nicotinic acetylcholine receptor ligands

ABSTRACT

The disclosure provides compounds of formula I, including their salts, as well as compositions and methods of using the compounds. The compounds are ligands for the nicotinic α7 receptor and may be useful for the treatment of various disorders of the central nervous system, especially affective and neurodegenerative disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This Continuation application claims the benefit of U.S. Ser. No.14/574,653 filed Dec. 18, 2014, now pending, which in turn is aContinuation application which claims the benefit of U.S. Ser. No.14/246,566 filed Apr. 7, 2014, now abandoned, which in turn is aContinuation application which claims the benefit of U.S. Ser. No.13/740,390 filed Jan. 14, 2013, now abandoned, which in turn is aContinuation application which claims the benefit of U.S. Ser. No.13/270,121 filed Oct. 10, 2011, now abandoned, which in turn is aContinuation application which claims the benefit of U.S. Ser. No.12/607,354 filed Oct. 28, 2009, now U.S. Pat. No. 8,309,577 which inturn is a Continuation-in-Part application which claims the benefit ofU.S. Ser. No. 12/423,299 filed Apr. 14, 2009, now U.S. Pat. No.7,863,291 which in turn claims the benefit of U.S. ProvisionalApplication Ser. No. 61/047,211 filed Apr. 23, 2008, now expired, herebyincorporated by reference in their entireties.

BACKGROUND OF THE INVENTION

The disclosure generally relates to compounds of formula I, includingtheir salts, as well as compositions and methods of using the compounds.The compounds are ligands, agonists and partial agonists for thenicotinic α7 receptor and may be useful for the treatment of variousdisorders of the central nervous system, especially affective andneurodegenerative disorders.

Schizophrenia is a serious mental disorder, affecting approximately 1%of the population. Its progressive course results in major impairment ofmental and social functioning and often leads to the development ofother pathologies. Susceptibility often runs in families, with bothgenetic and environmental factors thought to be important. The directand indirect costs of the disease are estimated in the tens of billiondollars annually in the U.S. alone.

Patients with schizophrenia have an elevated risk of suicide(approximately a 10% lifetime risk). They have a 2.5 fold increase inall-cause mortality, resulting in a 20% lowered life expectancy. Theonset of illness can result in cascade of unhealthy lifestyle factorsand behaviors that elevate the risk of various conditions andconsequently the risk of death.

The onset of schizophrenia is most often in late adolescence or earlyadulthood, and episodes recur throughout life. The disease ischaracterized by the expression of three distinct symptom domains:positive, negative and cognitive. Psychotic or positive symptoms includedelusions, hallucinations, thought disorder and paranoia. Negativesymptoms include negative affect, social withdrawal, and anhedonia.Cognitive dysfunction includes deficits in attention, working memory andexecutive function. The pathophysiology of schizophrenia is not wellunderstood, however, most experts believe it is a multi-factorialdisorder in which biological, genetic and environmental factors play arole. Most current therapies target the dopaminergic system and haveresulted in the suggestion that an excess of dopaminergicneurotransmission underlies at least some aspects of schizophrenia. Thistheory received further support from findings that drugs which increasethe levels of dopamine cause psychoses similar to the positive symptomsof the disease. Also, post mortem analysis of brains from schizophrenicpatients indicate increased numbers of D2 dopamine receptors. Althoughnewer antipsychotic agents, known as atypical antipsychotics, which areactive at several additional neurotransmitter receptors, have beenintroduced in the past decade, these agents still share efficacy againstthe D2 dopamine receptor. All currently-used agents also have majorlimitations. Although positive symptoms are generally reduced in amajority of patients, these drugs do little to relieve the negativesymptoms and cognitive deficits that are common and often mostdebilitating. In addition, antipsychotic agents have a number ofunwanted and limiting side effects.

Nicotine is among the few agents which have a positive effect oncognitive function. Many schizophrenics smoke; the rate in patients is2-4 times that of the general population, and up to 90% inschizophrenics who have been institutionalized do smoke. This smokinghabit has been characterized as a form of self-medication.

Nicotinic acetylcholine receptors (nAChR's) are pentameric ligand-gatedion channels which are widely expressed through the central andperipheral nervous system. These channels are fast-desensitizing calciumchannels which, when open, increase the intracellular concentration ofthe Ca⁺⁺ ion. Although there are 12 individual receptors, the mostabundant nicotinic receptors in the brain are α4β2 and α7. The α4β2complex has been identified as the “high affinity” nicotine site. Thehomo-pentameric α7 receptor selectively binds the natural product,α-bungarotoxin, which has allowed its relatively facile localization andmeasurement. The α7 receptor is primarily expressed in the cortex,hippocampus and subcortical limbic regions and commonly occurspre-synaptically. The localization of α7 nAChRs in areas involved withlearning and memory has led to studies using both knockout mice andpharmacological manipulation. It is involved in sensory gating, memory,and neuronal plasticity. Alpha7 agonists have been shown to increase therelease of neurotransmitters in rodents, including dopamine, serotonin,glutamate and GABA. Compounds which selectively bind to the α7 receptor,such as α7 agonists and partial agonists, have been shown to improvelearning and memory functions in normal and aged animals, reversescopolamine-induced memory deficits, reverse deficits in cognitioninduced by NMDA antagonists, reverse pharmacologically-induced gatingdeficits, e.g. amphetamine induced gating disruption, and to possesssome anxiolytic properties. The α7 agonists of the present invention areexpected to be useful in the treatment of schizophrenia and cognitivedisorders associated with schizophrenia.

Alzheimer's disease is a progressive neurodegenerative disorder,resulting in the general loss of cognitive functions. The incidenceincreases with age, to the degree that 25-50% of all individuals over 85are estimated to suffer from some degree of dementia. A diagnosis ofAlzheimer's implies that the remaining life expectancy is reduced byhalf, compared to normal adults.

Clinical signs of Alzheimer's disease are progressive cognitivedeterioration, decreased ability to perform the activities of dailyliving and neuropsychiatric symptoms or behavioral changes. In theadvanced stages of the disease, deterioration of musculature andmobility may lead to inability to feed oneself, and eventually to thepatient becoming bedridden. Language becomes severely disorganized, andthen is lost altogether. Patients are not able to perform even simpletasks independently and require constant supervision. The cost ofinstitutional care makes up nearly 70% of the cost of the disease.Therefore, therapies which increase cognitive function and delayinstitutionalization are greatly needed.

Alzheimer's disease has been shown in several studies to be accompaniedby a reduction in nicotinic receptors in the cortex and hippocampus.Nicotine injections or nicotine skin patches have been reported tosignificantly improve attention, memory and learning in Alzheimer'sdisease patients. While there is a progressive loss of nicotinicreceptors during the course of Alzheimer's disease, the α7 neurons arerelatively spared, compared to the more abundant α4 receptors. Recently,the administration of selective nicotinic α7 agonists has been shown toincrease cognitive functioning in Alzheimer's patients when dosed aslong as 8 weeks. This clinical data is consistent with pre-clinical datashowing α7 agonists and partial agonists improve learning and memoryfunctions in normal and aged animals and reverse scopolamine-inducedmemory deficits. Thus, the compounds of the present invention may beuseful in the treatment and prevention of Alzheimer's disease. Theamyloid peptide Aβ42 has been shown to bind to the α7 nicotinic receptor(Wang et al., J. Biol. Chem., 2000, 275:5626-5632; J. Neurochem. 2000,75:1155-1161). This association may facilitate the aggregation of Aβ42,believed to be important in the toxic effects of Aβ42, and may alsocause disregulation of signaling through α7 nicotinic receptors.Deletion of the α7 receptor gene improves cognitive deficits andsynaptic pathology in a mouse model of Alzheimer's disease(Dziewczapolski et al., J. Neuroscience, 2009, pp 8805-8815). Thecompounds of the present invention may disrupt the interaction of Aβ42and α7 receptors. Treatment with α7 agonists and partial agonists mayrepresent an approach for disease modification in Alzheimer's disease.Alpha7 receptors may also mediate inflammatory processes inneurodegenerative conditions, such as Alzheimer's disease(Conejero-Goldberg et al., Neurosci. and Biobehav. Rev., 2008, 32, pp693-706). The α7 agonists and partial agonists of the present inventionmay be useful in reducing inflammation in neurodegenerative diseases anddisorders, such as Alzheimer's disease.

The α7 receptor has also been shown to be involved in the reduction ofinflammation via the vagus nerve. In addition, the α7 receptor isexpressed in synoviocytes from RA and OA patients, and α7 agonists havebeen shown to inhibit the proinflammatory cascade that occurs in therheumatoid joint (Waldberger et al., Arthritis and Rheumatism, Vol 58,pp 3439-3449). Thus, the compounds of the present invention may beuseful in the treatment of inflammatory conditions, such as rheumatoidarthritis and osteoarthritis.

Nicotinic receptors containing the α7 subunit are present on mucosalmast cells known to be involved in gastrointestinal hypersensitivity(Kageyama-Yahara et al., Biochem and Biophys. Research Commun., 2008, v.377, pp321-325). The α7 agonist GTS-21 inhibits the antigen-induceddegranulation of mucosal mast cells, suggesting that α7 agonists may beuseful in the treatment of hypersensitive bowel conditions, such asulcerative colitis.

In a recent report (Marrero et al., JPET Fast Forward, Sep. 28, 2009,DOI: 10.1124/jpet.109.154633), an α7 agonist was shown to decreaseweight gain and food intake and reduce the elevated plasma levels oftriglycerides, glucose, glycated hemoglobin and TNFa in a mouse model oftype II diabetes (db/db mice which are deficit in leptin receptors). Theα7 agonists and partial agonists of the present invention may be usefulin the treatment of diabetes.

The following references provide general reviews of the nicotinicreceptor system and α7 receptors and ligands: Picciotto and Zoli, J.Neurobio. (2002) 53:641-655; Brening, et al, Ann. Reports in Med. Chem.(2005) 40:3-16; Dani and Bertrand, Ann. Rev. Pharm. Tox. (2007)47:699-729; Olincy and Stevens, Biochem. Pharmacol. (2007) 74:1192-1201;Broad, et al, Drugs Future (2007) 32 (2):161-70; de Jonge and Ulloa,Brit. J. Pharmacol. (2007) 151:915-929; Romanelli, et al, ChemMedChem(2007) 2(6):746-767; Lightfoot et al., Progress in Medicinal Chemistry(2008), v 46, pp131-171; Concotta et al., Current Opinion inInvestigational Drugs (2008), v 9, pp47-56; Leiser et al., Pharmacol.and Therapeutics (2009), doi:10:1016/j.pharmthera.2009.03.009).

Ligands for the nicotinic α7 receptor have been disclosed in thereferences above, and also in US patent application publication U.S.2007004715, WO 2008/000469, WO 2003/092580, WO 2004/000,469, EP 337,547,EP 452,101, and C. J. Swain, et al., J. Med. Chem., (1992) 35:1019-1031.

The invention provides technical advantages, for example, the compoundsare novel and are ligands for the nicotinic α7 receptor and may beuseful for the treatment of various disorders of the central nervoussystem, especially affective and neurodegenerative disorders.Additionally, the compounds provide advantages for pharmaceutical uses,for example, with regard to one or more of their mechanism of action,binding, inhibition efficacy, target selectivity, solubility, safetyprofiles, or bioavailability.

DESCRIPTION OF THE INVENTION

The invention encompasses compounds formula I, includingpharmaceutically acceptable salts, and compositions and methods oftreatment using these compounds. The compounds may be useful for thetreatment of various disorders of the central nervous system:

One aspect of the invention is a compound of formula I, or astereoisomer thereof,

wherein:R¹ is selected from the group consisting of isoxazolyl, pyrazolyl,oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl,pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, quinolinyl,isoquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, quinazolinyl,naphthyridinyl, indazolyl, indolyl, 2-indolonyl, benzisoxazolyl,benzoisothiazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl,furopyridinyl, thienopyridinyl, thienopyrimidinyl, isothiazolopyridinyl,thiazolopyridinyl, thiazolopyridinonyl, thiazolopyrazinyl,thiazolopyrimidinyl, triazolopyridinyl, triazolopyrazinyl,pyrrolotriazinyl, 5,6-dihydrobenzo[h]quinazolinyl,5H-chromeno[4,3-d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl,5,6,7,8-tetrahydroquinazolinyl, 7,8-dihydroquinazolin-5(6H)-onyl, andtetrahydrobenzothiazolyl, and is substituted with 0-3 substituentsindependently selected from the group consisting of C₁₋₄alkyl,C₃₋₇cycloalkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄haloalkoxy,C₃₋₇cycloalkoxy, C₁₋₄alkylthio, phenoxy, benzyloxy, halo, hydroxy,cyano, nitro, C₁₋₄alkylsulfonyl, NR²R³, pyrrolidinonyl, methylenedioxy,furyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, triazolyl, pyrazinyl,pyrimidinyl, naphthyl, C₁₋₄alkylamido, CONR²R³, pyridyl, phenyl, andbenzyl, and where imidazolyl, pyridyl, phenyl and benzyl are substitutedwith 0-2 substituents independently selected from the group consistingof halo, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl, C₁₋₄haloalkoxy, andNR²R³;R² is hydrogen, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, or C₁₋₄aminoalkyl;R³ is hydrogen, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, or C₁₋₄aminoalkyl;or R₂ and R₃ taken together with the nitrogen atom to which they areattached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,N—(C₁₋₄alkyl)piperazinyl, morpholinyl, or homopiperidinyl;or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is stereoisomer of formula I accordingto formula Ia.

Another aspect of the invention is a compound of formula I or Ia whereR¹ is selected from the group consisting of dimethylisoxazolyl,(methyl)(phenyl)isoxazolyl, methylpyrazolyl, dimethylpyrazolyl,thienylpyrazolyl, methoxyphenylpyrazolyl, thiazolyl, bromothiazolyl,cyanothiazolyl, methylthiazolyl, dimethylthiazolyl,(methyl)(phenyl)thiazolyl, isopropylthiazolyl, butylthiazolyl,benzylthiazolyl, methoxyphenylmethylthiazolyl, phenylthiazolyl,chlorophenylthiazolyl, methoxyphenylthiazolyl,(methoxyphenyl)(methyl)thiazolyl, pyridinylthiazolyl,(phenyl)(methyl)imidazolyl, methyloxadiazolyl, ethyloxadiazolyl,methylthiadiazolyl, fluorophenylthiadiazolyl, furylthiadiazolyl,(dimethylcarboxamido)(methyl)thiazolyl, (pyrrolidinylCO)thiazolyl,phenyltriazolyl, pyridinyl, bromopyridinyl, chloropyridinyl,(chloro)(fluoro)pyridinyl, (chloro)(methyl)pyridinyl, dichloropyridinyl,fluoropyridinyl, cyanopyridinyl, (cyano)(methyl)pyridinyl,(cyano)(dimethyl)pyridinyl, methoxypyridinyl,(methylpyrrolidinyl)pyridinyl, phenylpyridinyl,methoxypyridinylpyridinyl, pyridazinyl, bromopyridazinyl,chloropyridazinyl, methylpyridazinyl, methoxypyridazinyl,methylthiopyridazinyl, pyrrolidinylpyridazinyl,pyrrolidinonylpyridazinyl, phenylpyridazinyl, pyridinylpyridazinyl,methoxypyridinylpyridazinyl, pyrimidinyl, (bromo)(isopropyl)pyrimidinyl,(bromo)(dimethyl)pyrimidinyl, (bromo)(cyclopropyl)pyrimidinyl,(bromo)(methoxy)pyrimidinyl, (bromo)(phenyl)pyrimidinyl,(bromo)(pyridinyl)pyrimidinyl, chloropyrimidinyl,(chloro)(dimethyl)pyrimidinyl, (methyl)(methoxy)pyrimidinyl,methylpyrimidinyl, ethylpyrimidinyl, (methyl)(phenyl)pyrimidinyl,dimethylpyrimidinyl, butylpyrimidinyl, isopropylpyrimidinyl,cyclopropylpyrimidinyl, methoxypyrimidinyl, dimethoxypyrimidinyl,isopropoxypyrimidinyl, cyclopentoxypyrimidinyl,difluoromethoxypyrimidinyl, trifluoroethoxypyrimidinyl,phenoxypyrimidinyl, methylthiopyrimidinyl, phenylpyrimidinyl,chlorophenylpyrimidinyl, methylphenylpyrimidinyl,methoxyphenylpyrimidinyl, (phenyl)(triazolyl)pyrimidinyl,pyridinylpyrimidinyl, methoxypyridinylpyrimidinyl,methoxypyrimidinylpyrimidinyl, naphthylpyrimidinyl, pyrazinyl,bromopyrazinyl, (bromo)(methoxy)pyrazinyl, chloropyrazinyl,methylpyrazinyl, dimethylpyrazinyl, butylpyrazinyl, cyanopyrazinyl,methoxypyrazinyl, isopropoxypyrazinyl, trifluoromethylpyrazinyl, andphenylpyrazinyl, and dimethyltriazinyl; or a pharmaceutically acceptablesalt thereof.

Another aspect of the invention is a compound of formula I or Ia whereR¹ is selected from the group consisting of dimethylpyridinoisoxazolyl,benzoxazolyl, chlorobenzoxazolyl, fluorophenylbenzoxazolyl,ethylphenylbenzoxazolyl, dimethylaminophenylbenzoxazolyl,pyridinylbenzoxazolyl, benzothiazolyl, acetamidobenzothiazolyl,bromobenzothiazolyl, chlorobenzothiazolyl,(chloro)(methyl)benzothiazolyl, (chloro)(methoxy)benzothiazolyl,fluorobenzothiazolyl, difluorobenzothiazolyl, cyanobenzothiazolyl,methylbenzothiazolyl, dimethylbenzothiazolyl,(methyl)(methoxy)benzothiazolyl, ethylbenzothiazolyl,trifluoromethylbenzothiazolyl, hydroxybenzothiazolyl,methoxybenzothiazolyl, ethoxybenzothiazolyl, isopropoxybenzothiazolyl,trifluoromethoxybenzothiazolyl, difluoromethoxybenzothiazolyl,dimethoxybenzothiazolyl, morpholinylbenzothiazolyl,(pyrrolidinylCO)benzothiazolyl, methylsulfonylbenzothiazolyl,chlorothiazolopyridinyl, dimethylthiazolopyridinyl,benzyloxythiazolopyridinyl, difluoromethoxythiazolopyridinyl,benzotriazolyl, indolonyl, indazolyl, bromoindazolyl, chloroindazolyl,fluoroindazolyl, (methyl)(methoxy)indazolyl, methoxyindazolyl,trifluoromethylindazolyl, trifluoromethoxyindazolyl,difluoromethoxyindazolyl, benzimidazolyl, fluorobenzimidazolyl,methylbenzimidazolyl, (methyl)(methoxy)benzimidazolyl,methoxybenzimidazolyl, tetrahydrobenzothiazolyl, furopyridinyl,dimethylfuropyrimidinyl, thienopyrimidinyl, isopropylthienopyrimidinyl,dimethylthienopyrimidinyl, chlorotriazolopyridinyl,methyltriazolopyridinyl, trifluoromethyltriazolopyridinyl,methoxytriazolopyridinyl, triazolopyrazinyl, bromopyrrolotriazinyl,dimethylaminothiazolopyrimidinyl, thiazolopyazinyl,bromothiazolopyazinyl, methoxythiazolopyazinyl,methylthiothiazolopyazinyl, methoxythiazolopyrimidinyl,(methyl)(methoxy)thiazolopyrimidinyl, quinolinyl, bromoquinolinyl,fluoroquinolinyl, methylquinolinyl, (methyl)(methoxy)quinolinyl,isoquinolinyl, bromoisoquinolinyl, dichloroisoquinolinyl,methylisoquinolinyl, dimethylisoquinolinyl, quinoxalinyl,chloroquinoxalinyl, methylquinoxalinyl, methoxyquinoxalinyl,quinazolinyl, bromoquinazolinyl, naphthyridinyl,5,6-dihydrobenzo[h]quinazolinyl, 5H-chromeno[4,3-d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, 5,6,7,8-tetrahydroquinazolinyl,and 7,8-dihydroquinazolin-5(6H)-onyl; or a pharmaceutically acceptablesalt thereof

Another aspect of the invention is a compound of formula I or Ia whereR¹ is selected from the group consisting of phenylthiazolyl,(chloro)(methyl)pyridinyl, (bromo)(phenyl)pyrimidinyl,methoxypyrimidinyl, difluoromethoxypyrimidinyl,difluoroethoxypyrimidinyl, cyclopentoxypyrimidinyl,(methylphenyl)pyrimidinyl, (methoxyphenyl)pyrimidinyl, bromopyrazinyl,chloropyrazinyl, methylthiopyrazinyl, methoxybenzothiazolyl,ethoxybenzothiazolyl, difluoromethoxybenzothiazolyl,thiazolopyridinonyl, trifluoromethylindazolyl, benzimidazolyl,isoquinoinyl, and quinazolinyl or a pharmaceutically acceptable saltthereof.

Another aspect of the invention is a compound or formula I or Ia whereR¹ is selected from the group consisting of bromopyridinyl,dichloropyridinyl, methoxypyridinyl, (pyridinyl)pyridinyl,(phenyl)pyrimidinyl, (methoxypyridinyl)pyrimidinyl,(pyrazolyl)pyrimidinyl, chloropyrazinyl, (bromo)(chloro)pyrazinyl, andchlorobenzothiazolyl; or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound or formula I or Ia whereR¹ is selected from the group consisting of thiazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, benzothiazolyl, thiazolopyridinyl,indazolyl, benzimidazolyl, isoquinolinyl, and quinazolinyl, and issubstituted with 0-3 substituents independently selected from the groupconsisting of C₁₋₄alkyl, C₃₋₇cycloalkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy,C₁₋₄haloalkoxy, C₃₋₇cycloalkoxy, C₁₋₄alkylthio, phenoxy, benzyloxy,halo, hydroxy, cyano, C₁₋₄alkylsulfonyl, NR²R³, pyrrolidinonyl,methylenedioxy, furyl, thienyl, triazolyl, pyrimidinyl, naphthyl,C₁₋₄alkylamido, CONR²R³, pyridyl, phenyl, and benzyl, and where pyridyl,phenyl and benzyl are substituted with 0-2 substituents independentlyselected from the group consisting of halo, C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄haloalkyl, C₁₋₄haloalkoxy, and NR²R³; or a pharmaceuticallyacceptable salt thereof

Another aspect of the invention is a compound or formula I or Ia whereR¹ is selected from the group consisting of pyridinyl, pyrimidinyl,pyrazinyl, thiazolopyridinyl, and isoquinolinyl, and is substituted with0-3 substituents independently selected from the group consisting ofC₁₋₄alkyl, C₃₋₇cycloalkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄haloalkoxy,C₃₋₇cycloalkoxy, C₁₋₄alkylthio, phenoxy, benzyloxy, halo, hydroxy,cyano, C₁₋₄alkylsulfonyl, NR²R³, pyrrolidinonyl, methylenedioxy, furyl,thienyl, triazolyl, pyrimidinyl, naphthyl, C₁₋₄alkylamido, CONR²R³,pyridyl, phenyl, and benzyl, and where pyridyl, phenyl and benzyl aresubstituted with 0-2 substituents independently selected from the groupconsisting of halo, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl,C₁₋₄haloalkoxy, and NR²R³; or a pharmaceutically acceptable saltthereof.

Another aspect of the invention is a compound or formula I or Ia whereR¹ is selected from the group consisting of pyridinyl and isoquinolinyl,and is substituted with 0-3 substituents independently selected from thegroup consisting of C₁₋₄alkyl, C₃₋₇cycloalkyl, C₁₋₄haloalkyl,C₁₋₄alkoxy, C₁₋₄haloalkoxy, C₃₋₇cycloalkoxy, C₁₋₄alkylthio, phenoxy,benzyloxy, halo, hydroxy, cyano, C₁₋₄alkylsulfonyl, NR²R³,pyrrolidinonyl, methylenedioxy, furyl, thienyl, triazolyl, pyrimidinyl,naphthyl, C₁₋₄alkylamido, CONR²R³, pyridyl, phenyl, and benzyl, andwhere pyridyl, phenyl and benzyl are substituted with 0-2 substituentsindependently selected from the group consisting of halo, C₁₋₄alkyl,C₁₋₄alkoxy, C₁₋₄haloalkyl, C₁₋₄haloalkoxy, and NR²R³; or apharmaceutically acceptable salt thereof

Another aspect of the invention is a compound selected from the groupconsisting of

or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound selected from the groupconsisting of

or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula I where R₁ isselected from the group consisting of thiazole, thiadiazole, isoxazole,oxazole, pyrazole, imidazole, pyridine, pyrazine, pyridazine,pyrimidine, quinoline, isoquinoline, quinoxaline, indazole, indole,2-indolone, benzothiazole, benzimidazole, benzoxazole,benzo(d)isothiazole, benzisoxazole, isothiazolo-[5,4-b]pyridine,(1,2,4)-triazolo[1,5-a]pyridine, thiazolo[5,4-b]pyridine andtetrahydrobenzothiazole in which each group is optionally substitutedwith one or two substituents selected from the group consisting ofC₁₋₄alkyl, C₁₋₄alkoxy, halogen, hydroxy, cyano, trifluoromethyl,difluoromethyl, fluoromethyl, trifluoromethoxy, difluoromethoxy,C₁₋₄alkylsulfonyl, furyl, morpholino, methylenedioxy, pyridyl,C₁₋₄alkylphenyl, halophenyl, dimethylaminophenyl, C₁₋₄alkylamido,—CONR₂R₃ in which R₂ and R₃ each are independently hydrogen, C₁₋₄alkyl,hydroxy C₁₋₄alkyl, amino C₁₋₄alkyl or R₂ and R₃ taken together with theatom to which they are attached are C₃₋₆ cycloalkyl; phenyl, substitutedphenyl, phenylmethyl, substituted phenylmethyl in which said substitutedphenyl and substituted phenylmethyl are substituted with substituentsindependently selected from the group consisting of halogen, C₁₋₄alkyl,C₁₋₄alkoxy, trifluoromethyl and trifluoromethoxy; or a pharmaceuticallyacceptable salt thereof

For a compound of formula I or Ia, the scope of any instance of avariable substituent, including R¹, R², and R³, can be usedindependently with the scope of any other instance of a variablesubstituent. As such, the invention includes combinations of thedifferent aspects.

Unless specified otherwise, these terms have the following meanings“Alkyl” means a straight or branched alkyl group composed of 1 to 4carbons. “Alkenyl” means a straight or branched alkyl group composed of2 to 4 carbons with at least one double bond. “Alkynyl” means a straightor branched alkyl group composed of 2 to 4 carbons with at least onetriple bond. “Cycloalkyl” means a monocyclic ring system composed of 3to 7 carbons. “Haloalkyl” and “haloalkoxy” include all halogenatedisomers from monohalo to perhalo. Terms with a hydrocarbon moiety (e.g.alkoxy) include straight and branched isomers for the hydrocarbonportion. Parenthetic and multiparenthetic terms are intended to clarifybonding relationships to those skilled in the art. For example, a termsuch as ((R)alkyl) means an alkyl substituent further substituted withthe substituent R.

The invention includes all pharmaceutically acceptable salt forms of thecompounds. Pharmaceutically acceptable salts are those in which thecounter ions do not contribute significantly to the physiologicalactivity or toxicity of the compounds and as such function aspharmacological equivalents. These salts can be made according to commonorganic techniques employing commercially available reagents. Someanionic salt forms include acetate, acistrate, besylate, bromide,chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride,hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate,phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Somecationic salt forms include ammonium, aluminum, benzathine, bismuth,calcium, choline, diethylamine, diethanolamine, lithium, magnesium,meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium,tromethamine, and zinc.

Some of the compounds of the invention exist in stereoisomeric forms.The invention includes all stereoisomeric forms of the compoundsincluding enantiomers and diastereromers. Methods of making andseparating stereoisomers are known in the art.

The invention includes all tautomeric forms of the compounds. An exampleof a tautomeric pair is shown below.

The invention is intended to include all isotopes of atoms occurring inthe present compounds. Isotopes include those atoms having the sameatomic number but different mass numbers. By way of general example andwithout limitation, isotopes of hydrogen include deuterium and tritium.Isotopes of carbon include ¹³C and ¹⁴C. Isotopically-labeled compoundsof the invention can generally be prepared by conventional techniquesknown to those skilled in the art or by processes analogous to thosedescribed herein, using an appropriate isotopically-labeled reagent inplace of the non-labeled reagent otherwise employed. Such compounds mayhave a variety of potential uses, for example as standards and reagentsin determining biological activity. In the case of stable isotopes, suchcompounds may have the potential to favorably modify biological,pharmacological, or pharmacokinetic properties.

Synthetic Methods

The compounds may be made by methods known in the art including thosedescribed below and including variations within the skill of the art.Some reagents and intermediates are known in the art. Other reagents andintermediates can be made by methods known in the art using readilyavailable materials. The variables (e.g. numbered “R” substituents) usedto describe the synthesis of the compounds are intended only toillustrate how to make the compounds and are not to be confused withvariables used in the claims or in other sections of the specification.The following methods are for illustrative purposes and are not intendedto limit the scope of the invention.

Some of the compounds may be prepared using the reactions and techniquesdescribed in this section. The reactions are performed in solventsappropriate to the reagents and materials employed and are suitable forthe transformations being effected. It is understood by one skilled inthe art of organic synthesis that the functionality present on variousportions of the molecule must be compatible with the reagents andreactions proposed. Such restrictions to the substituents which arecompatible with the reaction conditions will be readily apparent to oneskilled in the art and alternate methods must then be used.

Abbreviations used in the schemes generally follow conventions used inthe art. Chemical abbreviations used in the specification and examplesare defined as follows: “NaHMDS” for sodium bis(trimethylsilyl)amide;“DMF” for N,N-dimethylformamide; “MeOH” for methanol; “NBS” forN-bromosuccinimide; “Ar” for aryl; “TFA” for trifluoroacetic acid; “LAH”for lithium aluminum hydride; “BOC”, “DMSO” for dimethylsulfoxide; “h”for hours; “rt” for room temperature or retention time (context willdictate); “min” for minutes; “EtOAc” for ethyl acetate; “THF” fortetrahydrofuran; “EDTA” for ethylenediaminetetraacetic acid; “Et₂O” fordiethyl ether; “DMAP” for 4-dimethylaminopyridine; “DCE” for1,2-dichloroethane; “ACN” for acetonitrile; “DME” for1,2-dimethoxyethane; “HOBt” for 1-hydroxybenzotriazole hydrate; “DIEA”for diisopropylethylamine, “Nf” for CF₃(CF₂)₃SO₂—; and “TMOF” fortrimethylorthoformate.

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq” forequivalent or equivalents, “g” for gram or grams, “mg” for milligram ormilligrams, “L” for liter or liters, “mL” for milliliter or milliliters,“μL” for microliter or microliters, “N” for normal, “M” for molar,“mmol” for millimole or millimoles, “min” for minute or minutes, “h” forhour or hours, “rt” for room temperature, “RT” for retention time, “atm”for atmosphere, “psi” for pounds per square inch, “conc.” forconcentrate, “sat” or “sat′d” for saturated, “MW” for molecular weight,“mp” for melting point, “ee” for enantiomeric excess, “MS” or “MassSpec” for mass spectrometry, “ESI” for electrospray ionization massspectroscopy, “HR” for high resolution, “HRMS” for high resolution massspectrometry, “LCMS” for liquid chromatography mass spectrometry, “HPLC”for high pressure liquid chromatography, “RP HPLC” for reverse phaseHPLC, “TLC” or “tlc” for thin layer chromatography, “NMR” for nuclearmagnetic resonance spectroscopy, “¹H” for proton, “δ” for delta, “s” forsinglet, “d” for doublet, “t” for triplet, “q” for quartet, “m” formultiplet, “br” for broad, “Hz” for hertz, and “α”, “β”, “R”, “S”, “E”,and “Z” are stereochemical designations familiar to one skilled in theart.

Compounds of Formula I are prepared as illustrated in Reaction Scheme 1.The ketone of Formula III (3-quinuclidone) is known, is commerciallyavailable, or may be prepared by methods known to those skilled in theart. The ketone can be converted to the corresponding cyanohydrin ofFormula IV by reaction with sodium or potassium cyanide plus an acid.The compound of Formula IV can be reduced to the correspondingamino-methyl compound (borane complex) of Formula V by reaction withborane/tetrahydrofuran complex.

The compound of Formula V can be reacted with heteroaryl isothiocyanatesdirectly in an inert solvent to give the thioureas of Formula VI.Alternatively, the heteroarylamine can be reacted withthiocarbonyl-diimidazole to give an activated species which can be usedwithout isolation to convert the compound of Formula V to the compoundof Formula VI. The heteroarylamine may be prepared by methods known tothose skilled in the art.

The thiourea of Formula VI can be cyclized using, for example,di-isopropyl carbodiimide to give the oxazoline of Formula VII which maybe deprotected via treatment with acid to give the racemic final productof the compound of Formula I. The compound of Formula I may be resolvedinto pure enantiomer compounds of Formula Ia and Formula Ib by meansknown in the art, for example, via chiral chromatography.

Alternatively, the free amino group of the quinuclidine of Formula V canbe blocked with, for example, carbobenzyloxy-chloride (“CBZ-Cl”) to givethe compound of Formula VIII, as illustrated in Reaction Scheme 2.

The racemic compound of Formula VIII can be resolved into itsenantiomers, Formula IX and Formula X by, for example, chiralchromatography. Either the compound of Formula IX or Formula X, andpreferably the compound of Formula X, can then be carried on as shown inReaction Scheme 2.

The borane group in the compound of Formula X can be removed, forexample, by treatment with dilute hydrochloric acid, and thecarbobenzyloxy group can be removed, for example, by catalytichydrogenation to give the chiral quinuclidine amine of Formula XI.Similarly to Reaction Scheme 1, the amine salt of Formula XI can bereacted with isothiocyanates to give the thiourea of Formula VIa, whichcan then be reacted with dialkyl carbodiimides or mixed thioureas (asfrom reaction with thiocarbonyl diimidazole) to give the chiraloxazoline quinuclidine compounds of Formula Ia, and its tautomer,Formula IIa.

Alternatively, the borane group of V may be removed with hydrochloricacid to give dihydrochloride salt XII, which can be reacted in thepresence of base with an isothiocyanate to give intermediate thioureaXIII, which can then be cyclized as in Reaction Schemes 1-2 to give I.XII may also be prepared by other methods, as referenced in U.S. Pat.No. 5,137,895 (Aug. 11, 1992).

Additionally, the (hetero) aromatic amines may be reacted with carbondisulfide, sodium hydroxide, and methyl iodide to give intermediatedimethyl carbonimidodithioates XIV. These are reacted withdihydrochloride XI in the presence of base to eliminate two moles ofmethanethiol and generate desired products Ia directly.

Biological Methods I) α7 Nicotinic Ace Choline Receptor Binding.

Membranes were prepared for binding using HEK293 cells stably expressingthe rat α7 nicotinic acetycholine receptor (rat α7 nAChR). Cells werehomogenized at 4° C. in hypotonic lysis buffer consisting of 10 mM Tris(pH 7.4), 5 mM EDTA and protease inhibitors and centrifuged at 32000×gfor 20 minutes. The pellet was washed once in membrane wash bufferconsisting of 50 mM Tris (pH 7.4), 1 mM EDTA and protease inhibitors andcentrifuged at 32000×g for 20 minutes. This pellet was then resuspendedin assay buffer consisting 50 mM KH₂PO₄ (pH 7.4 at 25° C.), 1 mM EDTA,0.005% Triton-X 100 and 0.1% (v/v) Sigma Protease Inhibitor Cocktail.Aliquots were then frozen in dry ice/ethanol and kept at −80° C. untilthe day of the assay.

II) A Ca²⁺-Sensitive, Fluorescence-Based Assay α-7 for NicotinicAcetylcholine Receptor Channel Function in Mammalian Cells (“FLIPR”).

Summary:

Lead compounds are evaluated for agonist activity at α-7, α3β4, α4αβ2,and α1β1δ1ε sub-types of nicotinic ACh receptor ion channels expressedin mammalian HEK 293 cells. Agonist potency and efficacy values aredetermined from kinetic fluorescence Ca²⁺ influx measurements made usinga 384 well FLIPR (Fluorescence Image Plate Reader). The utility offluorescent indicators for measuring changes in intracellular divalentcation concentrations, particularly Ca²⁺, for drug discovery endeavorsis well documented (Rudiger, R., et al., Nature Reviews, 2003,4:579-586; Gonzalez J. E., et al., Receptors and Channels, 2002,8:283-295). In this assay, channel expressing HEK cell lines seeded in384 well assay plates are loaded with a membrane permeant fluorescentCa²⁺ indicator dye, whose 510 nm green emission signal increases inresponse to elevation of intracellular Ca²⁺ concentration. The basalfluorescence from the cells is monitored in real time, followed by theacute addition of test compounds. If the compound is an agonist at anyof the non-selective cation channels, the latter open and allow themovement of extracellular Ca²⁺ ions into the cell cytoplasm, where theybind to the Ca²⁺ indicator dye, and produce an increase in fluorescenceoutput signal, which is detected by a cooled CCD imaging camera.

Materials and Methods:

Reagents: The acetomethoxy (AM) ester of the Ca²⁺ indicator dye Fluo-4was obtained from InVitrogen, (Carlsbad, Calif.). Acetylcholine and allbuffer constituents were purchased from Sigma Chemical Company, St.Louis, Mo. G418 and Minimal Essential Medium were purchased fromInVitrogen Life Technologies, Carlsbad, Calif. Fetal bovine serum waspurchased from (InVitrogen, Carlsbad, Calif.).

Cell Culture:

HEK-293 cells were grown in Minimal Essential Medium containing 10%(v/v) fetal bovine serum at 37° C. in a 5% CO₂ incubator. HEK-293 cellsstably expressing the ion channels were grown in the same medium withthe addition of 500 μg/ml G418.

Ca²⁺ flux assays of Ca²⁺ channels expressed in HEK-293 cells:

HEK-293 cells expressing the ion channels of interest were plated in 384well, black-walled, clear-bottomed, poly-D-lysine coated plates at adensity of ˜20,000 cells/well in 20 μl of Minimal Essential Mediumcontaining 10% (v/v) fetal bovine serum and incubated for 2 days at 29°C. in a 5% CO₂ incubator. Prior to assay, cells were loaded with theFluo-4 AM ester. Cell loading was accomplished by removing the culturemedium and replacing it with 30 μl/well of the AM ester of the dye (5μM) mixed with Hanks Balanced Salt Solution (#14175-095) containing 20mM HEPES, 2.5 mM probenecid, 0.5 mM CaCl₂, 1 mM MgCl2 and 10 μMatropine. Dye loading was allowed to proceed for 90 minutes at roomtemperature at which time the dye loading solution was removed andreplaced with 40 μl/well of Hanks buffer. Cells loaded with dye wereloaded onto a FLIPR384 (Molecular Devices, Sunnyvale, Calif.). Fluo-4dye was excited using the 488 nm line of an argon laser. Emission wasfiltered using a 540+/−30 nm bandpass filter. For evaluation of theeffects of test compounds using the Ca²⁺ flux assay, compounds to betested were provided in assay ready plates. For nicotinic receptor ionchannel expressing cells, the assay was initiated by the addition of 20μl/well of Hanks buffer containing test compounds. For all assays, datawere collected at 1 Hz for 10 seconds (baseline), at which time thecompound containing stimulus buffers are added, and further measurementscollected at 0.33 Hz for 3 min.

Data Analysis:

The statistical robustness of the nicotinic receptor Ca²⁺ flux assays isdetermined from blanks and totals wells. The totals wells define maximalchannel activation for each compound test plate (Maximum efficaciousdose of acetylcholine), and the blanks wells which contain matched DMSOonly, define zero channel activation. The raw fluorescence units datafiles generated on the FLIPR plate reader are automatically exported andprocessed by in-house data analysis tools. The reduced percentactivation data for each concentration of test compound are fit usingMathIQ fitting engine (ID Business Solutions Limited, Surrey, UK). Datawere analyzed by fitting maximum amplitudes of change in fluorescence,for Ca²⁺ flux for a given condition of test compound. Potencies (EC₅₀values) of compounds are calculated from the average of three assaywells from a twenty point CRC. Test compound efficacy values (Ymaxvalues) are expressed relative to a maximal response to acetylcholine inthe total wells.

III) Fos Quantification Assay:

Male Wistar rats are treated with drug (1-10 mg/kg) or vehicle (2 ml/kg,sc). Two hours after treatments, the rats are rapidly decapitated anddiscrete brain regions of interest are isolated on ice and weighed andflash frozen with liquid nitrogen and stored at −80 deg. C. Furtherprocessing of the brain tissue for nuclear extracts as well as for Fosquantification are in accordance with the protocol prescribed by acommercially available ELISA-based chemiluminescence detection kit(catalog #89860, EZ-detect c-Fos Trans kit, Pierce Biotechnology Inc.,Rockford, Ill.).

IV) MK-801 Disrupted Set-Shift Assay in Rats:

This assay uses a modification of the protocol described by Stefani etal. (Behavioral Neuroscience, 2003, 117: 728-737). Test compounds areassessed for their ability to reverse an MK-801-induced performancedeficit (0.03 mg/kg, i.p., single dose) in this assay.

The activity of specific compounds described herein and tested in theabove assay (II) is provided in Table 1.

TABLE 1

FLIPR α7 Exam- FLIPR activity^(a) ple α7 rating Num- (EC₅₀, (EC₅₀, berR₁ nM) nM)  1

+++  1a

+  1b

+++  2

++  2a

+  2b

++  3

3840 +  4

+++  4a

+  4b

 230 ++  5

++  5a

+  5b

+++  6

++  6a

4340 +  6b

+++  7

++  7a

+  7b

+++  8

++  8a

 120 ++  8b

+  9

++  9a

7315 +  9b

+++  10

++  10a

++  10b

++  11

++  11b

 213 ++  12

++  12a

++  12b

+  13

+++  13a

++  13b

+++  14

++  14b

++  15

++  15a

6345 +  15b

++  16

++  16a

3174 +  16b

++  17

++  18

3930 +  19

++  20

++  20a

++  20b

 318 ++  21

+++  22

++  23

+++  24

+++  25

 510 ++  26

+++  27

+++  28

4010 +  29

++  30

++  31

++  32

++  34

+  35

4035 +  36

++  37

+  38

+++  39

+++  40

+++  41

+++  42

+++  43

+++  44

++  45

++  46

2000 +  47

+++  48

 790 ++  49

3330 +  50

+++  51

NT^(b)  52

 325 ++  53

+  54

+  55

+  56

+  57

3900 +  58

+  59

4240 +  60

2550 +  61

++  62

+  63

2600 +  64

+++  65

+  66

 360 ++  67

+  68

+  70

++  71

+  72

+  73

7550 +  74

+++  75

+  76

++  77

 355 ++  78

+  81

NT^(b)  82

NT^(b)  83

 240 ++  85

+  86

+  87

+++  88

++  89

+++  90

 130 ++  91

++  92

+++  93

++  94

+++  95

++  96

+  97

++  98

+  99

++ 100

+++ 101

++ 102

+++ 103

 280 ++ 104

++ 105

++ 106

++ 107

++ 108

NT^(b) 109

++ 110

 450 ++ 111

++ 112

+++ 113

+++ 114

++ 115

+ 116

+ 117

++ 118

+ 119

+++ 120

 875 ++ 121

+ 122

+++ 123

+ 124

+ 125

 17 +++ 126

+++ 127

+ 128

+++ 129

++ 130

++ 131

+ 132

++ 133

+++ 134

+++ 135

+++ 136

+++ 137

 137 ++ 138

+ 139

 16 +++ 140

++ 141

  4 +++ 142

++ 143

++ 144

+++ 145

+ 146

++ 147

++ 148

+ 149

 17 +++ 150

++ 151

++ 152

 233 ++ 153

++ 154

+ 155

++ 156

++ 157

++ 158

 135 ++ 159

+++ 160

+ 161

+ 162

+ 163

+++ 164

++ 165

 13 +++ 166

 11 +++ 167

+ 168

+++ 169

+ 170

+++ 171

+++ 172

++ 173

++ 174

 245 ++ 175

++ 176

++ 177

+++ 178

 17 +++ 179

++ 180

++ 181

 13 +++ 182

++ 183

+++ 184

+ 185

+ 186

++ 187

 424 ++ 188

+ 189

++ 190

+ 191

+++ 192

++ 193

 17 +++ 194

 18 +++ 195

+ 196

 13 +++ 197

+++ 198

 15 +++ 199

+ 200

+++ 201

+++ 202

 16 +++ 203

+++ 204

++ 205

++ 206

+ 207

++ 208

+ 209

+++ 210

  9 +++ 211

++ 212

+ 213

  9 +++ 214

+++ 215

+++ 216

+ 217

+ 218

 285 ++ 219

+ 220

+++ 221

++ 222

++ 223

++ 224

++ 225

++ 226

+++ 227

++ 228

+++ 229

+++ 230

+++ 231

++ 232

++ 233

+++ 234

+++ 235

+ 236

+ 237

+++ 238

 16 +++ 239

 15 +++ 240

++ 241

+ 242

++ 243

+ 244

+++ 245

+++ 246

+++ 247

++ 248

++ 249

+ 250

+++ 251

+++ 252

+++ 253

+++ 254

++ 255

++ 256

+++ 257

+++ 258

+ 259

+ 260

++ 261

+++ 262

+ 263

+++ 264

++ 265

+++ 266

+ 267

+++ 268

+++ 269

+ 270

+++ 271

+++ 272

+++ 273

+ 274

+ 275

++ 276

+++ 277

+++ 278

+++ 279

++ 280

281

+++ 282

++ 283

++ 284

+++ 285

++ 286

++ 287

++ 288

+++ 289

+++ 290

+++ 291

+++ 292

+++ 293

++ 294

+++ 295

++ ^(a)Activity based on EC₅₀ nM values: +++ = <100 nM; ++ = 100-1000nM; + = 1000-100000 nM; ^(b)NT = Not tested; NA = Not active (>1000000nM).

TABLE Ib

FLIPR α7 activity^(a) Example FLIPR α7 rating Number R₁ (EC₅₀, nM)(EC₅₀, nM) 296

+++ 297

 35 +++ 298

 25 +++ 299

+++ 300

+++ 301

+++ 302

 9 +++ 303

+++ 304

+++ 305

+++ 306

+++ 307

+++ 308

 59 +++ 309

+++ 310

+++ 311

+++ 312

+++ 313

+++ 314

+++ 315

+++ 316

+++ 317

660 ++ 318

+++ 319

+++ 320

+++ 321

+++ 322

+++ 323

+++ 324

+++ 325

139 ++ 326

++ 327

++ 328

++ 329

+++ 330

+++ 331

+++ 332

+++ 333

+++ 334

+++ 335

104 ++ 336

+++ 337

++  338A

+++  338B

+++ 339

+++ 340

+++ 341

+++ 342

1600  + 343

+++ 344

+++ 345

+++ 346

310 ++ 347

+++ 348

+++ 349

+++ 350

NT 351

+++ 352

560 ++ ^(a)Activity based on EC₅₀ nM values: +++ = <100 nM; ++ =100-1000 nM; + = 1000-100000 nM; ^(b)NT = Not tested; NA = Not active(>1000000 nM).

Pharmaceutical Compositions and Methods of Treatment

Compounds of formula I bind to alpha 7 and can be useful in treatingaffective disorders and neurodegenerative disorders. Therefore, anotheraspect of the invention is a composition comprising a compound offormula I, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.

Another aspect of the invention is the use of a compound of formula I inthe manufacture of a medicament for the treatment of affective disordersor neurodegenerative disorders.

Another aspect of the invention is the use of a compound of formula I inthe manufacture of a medicament for the treatment of schizophrenia orAlzheimer's Disease.

Another aspect of the invention is a method of treating affectivedisorders or neurodegenerative disorders comprising administering to apatient a therapeutically effective amount of a compound of formula I.

Another aspect of the invention is a method of treating schizophrenia orAlzheimer's Disease comprising administering to a patient atherapeutically effective amount of a compound of formula I.

Another aspect of the invention is a method of treating schizophreniacomprising administering to a patient a therapeutically effective amountof a compound of formula I.

Another aspect of the invention is a method of treating Alzheimer'sDisease comprising administering to a patient a therapeuticallyeffective amount of a compound of formula I.

Another aspect of the invention is a method of treating cognitivedisorders comprising administering to a patient a therapeuticallyeffective amount of a compound of formula I.

Another aspect of the invention is a method of treating rheumatoidarthritis comprising administering to a patient a therapeuticallyeffective amount of a compound of formula I.

Another aspect of the invention is a method of treating osteoarthritiscomprising administering to a patient a therapeutically effective amountof a compound of formula I.

Another aspect of the invention is a method of treating ulcerativecolitis comprising administering to a patient a therapeuticallyeffective amount of a compound of formula I.

Another aspect of the invention is a method of treating Crohn's Diseasecomprising administering to a patient a therapeutically effective amountof a compound of formula I.

Another aspect of the invention is a method of treating diabetescomprising comprising administering to a patient a therapeuticallyeffective amount of a compound of formula I.

“Patient” means a person suitable for therapy as understood bypractitioners in the field of affective disorders and neurodegenerativedisorders.

“Treatment,” “therapy,” and related terms are used as understood bypractitioners in the field of affective disorders and neurodegenerativedisorders.

The compounds of this invention are generally given as pharmaceuticalcompositions comprised of a therapeutically effective amount of acompound or its pharmaceutically acceptable salt and a pharmaceuticallyacceptable carrier and may contain conventional excipients.Pharmaceutically acceptable carriers are those conventionally knowncarriers having acceptable safety profiles. Compositions encompass allcommon solid and liquid forms including for example capsules, tablets,losenges, and powders as well as liquid suspensions, syrups, elixers,and solutions. Compositions are made using common formulationtechniques, and conventional excipients (such as binding and wettingagents) and vehicles (such as water and alcohols) are generally used forcompositions. See, for example, Remington's Pharmaceutical Sciences,Mack Publishing Company, Easton, Pa., 17th edition, 1985.

Solid compositions are normally formulated in dosage units andcompositions providing from about 1 to 1000 mg of the active ingredientper dose are preferred. Some examples of dosages are 1 mg, 10 mg, 100mg, 250 mg, 500 mg, and 1000 mg. Generally, other agents will be presentin a unit range similar to agents of that class used clinically.Typically, this is 0.25-1000 mg/unit.

Liquid compositions are usually in dosage unit ranges. Generally, theliquid composition will be in a unit dosage range of 1-100 mg/mL. Someexamples of dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100mg/mL. Generally, other agents will be present in a unit range similarto agents of that class used clinically. Typically, this is 1-100 mg/mL.

The invention encompasses all conventional modes of administration; oraland parenteral methods are preferred. Generally, the dosing regimen willbe similar to other agents used clinically. Typically, the daily dosewill be 1-100 mg/kg body weight daily. Generally, more compound isrequired orally and less parenterally. The specific dosing regime,however, will be determined by a physician using sound medicaljudgement.

DESCRIPTION OF SPECIFIC EMBODIMENTS

¹H-NMR spectra were run on a Bruker 500, 400, or 300 MHz instrument andchemical shifts were reported in ppm (8) with reference totetramethylsilane (δ=0.0). All evaporations were carried out underreduced pressure. Unless otherwise stated, LC/MS analyses were carriedout on a Shimadzu instrument using a Phenomenex-Luna 4.6×50 mm S 10reverse phase column employing a flow rate of 4 mL/min using a 0.1% TFAin methanol/water gradient [0-100% in 3 min, with 4 min run time] and aUV detector set at 220 nm or Gemini C18 4.6×50 mm 5u reverse phasecolumn employing a flow rate of 5 mL/min using a 10 mM ammonium acetateacetonitrile/water gradient [5-95% in 3 min, with 4 min run time] and aUV detector set at 220 nm (negative-ion mass spectrometry). Unlessotherwise stated, purification could be done by preparative C-18 columnemploying gradients of methanol-water containing 0.1% of trifluoroaceticacid (TFA), and using a Shimadzu High Performance Liquid PreparativeChromatographic System employing an XTERRA 30×100 mm S5 column at 40mL/min flow rate with a 12 min gradient.

Example 1N-(benzo[d]thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: N-(Benzo[d]thiazol-2-yl)-¹H-imidazole-1-carbothioamide

To benzo[d]thiazol-2-amine (20 g, 133 mmol) in acetonitrile (300 mL) wasadded 1,1′-thiocarbonyldiimidazole (30.8 g, 173 mmol). The reaction wasstirred at 50° C. for 24 hours. The reaction was cooled to roomtemperature and the precipitate was filtered and washed withacetonitrile (2×50 mL). The yellow powder was dried in a vacuum oven(40° C.) for 2 hours. The product,N-(benzo[d]thiazol-2-yl)-¹H-imidazole-1-carbothioamide (28.9 g, 111mmol), was taken directly to the next step without any furtherpurification.

Step B:(3-((3-Benzo[d]thiazol-2-ylthioureido)methyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate

To N-(benzo[d]thiazol-2-yl)-¹H-imidazole-1-carbothioamide (9.2 g, 35mmol) in N,N-dimethylformamide (100 mL) was added(3-(aminomethyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(6.0 g, 35 mmol) which was synthesized according to Swain C. J., et.al., J. Med. Chem., 35:1019-1031 (1992). The reaction was stirred at 65°C. for 15 hours. The reaction was cooled and concentrated to yield thecrude product. The crude material was purified via flash chromatography(50-100% ethyl acetate/hexanes) yielding the first spot/fractionsdetected by TLC as the product. The fractions were combined andconcentrated to yield(3-((3-benzo[d]thiazol-2-ylthioureido)methyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(10.6 g, 29.1 mmol, 83% yield) as an off-white powder. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 11.88 (s, 1H), 10.30 (s, 1H), 7.94 (d, J=7.63 Hz, 1H),7.55-7.74 (m, 1H), 7.37-7.53 (m, J=7.32, 7.32 Hz, 1H), 7.16-7.37 (m,J=7.63, 7.63 Hz, 1H), 5.39 (s, 1H), 3.85 (d, 2H), 2.65-3.08 (m, 6H),1.99-2.22 (m, 1H), 1.79-1.97 (m, 2H), 1.66-1.79 (m, 1H), 1.08-1.63 (m,4H). MS (LC/MS) R.T.=3.40; [M+H]⁺=363.1

Step C:(2-(Benzo[d]thiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate

To(3-((3-benzo[d]thiazol-2-ylthioureido)methyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(10.6 g, 29.1 mmol) in N,N-dimethylformamide (100 mL) was addedN,N′-diisopropylcarbodiimide (11.4 mL, 72.8 mmol). The reaction wasstirred at 70° C. for 4 hours. The reaction was concentrated to yield acrude residue. A small amount of ethyl acetate (20 mL) was added and thesuspension was sonicated. The solids were filtered and washed with smallportions of ethyl acetate (2×10 mL). The solids were dried in a vacuumoven (80° C.) to yield(2-(benzo[d]thiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate(6.83 g, 20.8 mmol, 72% yield) as a white powder. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 9.09 (br. s., 1H) 7.81 (d, J=7.63 Hz, 1H) 7.63 (d, J=7.93Hz, 1H) 7.30-7.40 (m, 1H) 7.15-7.24 (m, 1H) 3.88 (d, J=10.38 Hz, 1H)3.77 (d, J=10.38 Hz, 1H) 3.25-3.37 (m, 1H) 3.17 (dd, J=14.95, 1.83 Hz,1H) 2.99-3.10 (m, 1H) 2.79-2.98 (m, 3H) 2.27 (br. s., 1H) 1.98-2.11 (m,1H) 1.71-1.88 (m, 3H) 1.45 (br. s., 3H). MS (LC/MS) R.T.=2.44;[M+H−BH₃]⁺=315.1.

Step D:N-(Benzo[d]thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To(2-(benzo[d]thiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate(6.6 g, 20.1 mmol) in acetone (9 mL) was added 3M HCl (50.3 mL, 151mmol). The reaction was stirred at room temperature for 4 hours. Thereaction was complete by TLC (lower spot). Ethyl acetate was added andthe aqueous layer was then separated. The aqueous layer was neutralizedwith 1N sodium hydroxide. The product was extracted with ethyl acetate(2×150 mL). The organics were combined, dried with magnesium sulfate,filtered, and concentrated in vacuo to afford a white powder. A smallamount of ethyl acetate (20 mL) was added to the powder. The solids weresonicated and filtered to yield racemicN-(benzo[d]thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(5.13 g, 16.3 mmol, 81% yield) as a white powder. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 9.02 (br. s., 1H) 7.79 (d, J=7.02 Hz, 1H) 7.62 (d, J=7.63Hz, 1H) 7.29-7.38 (m, 1H) 7.15-7.22 (m, 1H) 3.90 (d, J=10.07 Hz, 1H)3.65 (d, J=10.07 Hz, 1H) 2.98-3.10 (m, 2H) 2.73-2.88 (m, 2H) 2.67 (t,J=7.78 Hz, 2H) 2.07 (br. s., 1H) 1.93 (br. s., 1H) 1.42-1.67 (m, 3H). MS(LC/MS) R.T.=1.15; [M+H]⁺=315.3.

The enantiomers were separated using a Chiralpak AD-H (3×25 cm, 5 uM)column with a mobile phase consisting of CO₂/methanol/ACN/DEA=70/30/0.1(v/v/v))=77/23. The wavelength was set at 300 nM. The separated peakswere concentrated in vacuo to yield white powders. The first peak offthe column was(S)—N-(benzo[d]thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(1.45 g, 4.61 mmol, 29.4% yield). (1a; S-isomer): ¹H NMR (400 MHz,DMSO-d₆) δ ppm 9.03 (br. s., 1H) 7.78 (d, J=7.05 Hz, 1H) 7.61 (d, J=7.55Hz, 1H) 7.27-7.37 (m, 1H) 7.11-7.23 (m, 1H) 3.89 (d, J=10.07 Hz, 1H)3.64 (d, J=10.07 Hz, 1H) 2.96-3.09 (m, 2H) 2.71-2.88 (m, 2H) 2.66 (t,J=7.81 Hz, 2H) 2.02-2.11 (m, 1H) 1.85-1.97 (m, 1H) 1.41-1.65 (m, 3H). MS(LC/MS) R.T.=1.15; [M+H]⁺=315.3. Optical rotation (1.23 mg/mL,DMSO)=+5.20°. The second peak was(R)—N-(benzo[d]thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(1.21 g, 3.85 mmol, 24.5% yield). (1b; R-isomer): ¹H NMR (500 MHz,DMSO-d₆) δ ppm 9.02 (br. s., 1H) 7.79 (d, J=7.32 Hz, 1H) 7.62 (d, J=7.63Hz, 1H) 7.33 (t, J=7.63 Hz, 1H) 7.18 (t, J=7.48 Hz, 1H) 3.90 (d, J=10.07Hz, 1H) 3.65 (d, J=10.07 Hz, 1H) 2.98-3.10 (m, 2H) 2.73-2.87 (m, 2H)2.67 (t, J=7.63 Hz, 2H) 2.08 (br. s., 1H) 1.93 (br. s., 1H) 1.42-1.67(m, 3H). MS (LC/MS) R.T.=1.15; [M+H]⁺=315.3; Optical rotation (3.9mg/mL, DMSO)=−3.92°.

Example 2N-(5-Methoxythiazolo[5,4-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 5-Methoxythiazolo[5,4-b]pyridin-2-amine

In a 500 ml, 3-neck flask equipped with a mechanical stirrer, droppingfunnel and thermometer, acetic acid (100 mL) was added and cooled in anice bath. Potassium thiocyanate (40 g, 412 mmol) and6-methoxypyridin-3-amine (6.2 g, 49.9 mmol) were added to the reactionmixture. The reaction was cooled in an ice-salt bath until the reactiontemperature reached <0° C. A solution of bromine (8 mL, 156 mmol) inacetic acid (30.0 mL) was added dropwise over 2 hours at a rate thatmaintained the reaction temperature <0° C. Mechanical stirring wasrequired. After the addition was complete, the mixture was left to stirand allowed to slowly warm to room temperature overnight. Water (30 mL)was then added and the mixture was heated to 85° C. in an oil bath. Thismixture was then filtered while still hot. The orange filter cake wasreturned to the reaction flask, and an additional 50 ml acetic acid wasadded. The mixture was heated again to 85° C., and then filtered whilestill hot once more. The combined filtrates were cooled in an ice bathand neutralized to pH 8 with conc. ammonium hydroxide. A purpleprecipitate formed which was then collected by filtration to afford 5 gof crude material. This crude material was recrystallized from methanol(40 mL) to yield 5-methoxythiazolo[5,4-b]pyridin-2-amine (3 g, 16.55mmol, 33.1% yield) as purple crystals. ¹H NMR (300 MHz, DMSO-d₆) δ ppm7.60 (1H, d, J=8.42 Hz), 7.41 (2H, s), 6.67 (1H, d, J=8.78 Hz), 3.81(3H, s).

Step B:(3-Hydroxy-3-((3-(5-methoxythiazolo[5,4-b]pyridin-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate

5-Methoxythiazolo[5,4-b]pyridin-2-amine (2.4 g, 13.24 mmol) was dividedamong 5×20 mL screw-cap vials. To each vial was added acetonitrile (10mL) and thiocarbonyl diimidazole (600 mg). All vials were heated at 60°C. overnight. The reaction vials were combined and concentrated to yieldcrudeN-(5-methoxythiazolo[5,4-b]pyridin-2-yl)-1H-imidazole-1-carbothioamideproduct.

This crude product was suspended in N,N-dimethylformamide (50 ml) and(3-(aminomethyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(2.7 g, 15.88 mmol) was then added. The reaction was heated at 70° C.for 4 hours. LC/MS showed essentially complete conversion. The reactionwas cooled to room temperature and then poured into water. The productwas extracted first with toluene, and then with chloroform. The organicswere combined, washed with water and brine, dried over sodium sulfate,filtered and concentrated in vacuo to afford crude material. This crudematerial was purified via flash chromatography (20-100% ethylacetate-hexane). The product fractions were collected and concentratedin vacuo to afford(3-hydroxy-3-((3-(5-methoxythiazolo[5,4-b]pyridin-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(1.36 g, 3.46 mmol, 26.1% yield). ¹HNMR showed a 1:0.55 molar ratio of(3-hydroxy-3-((3-(5-methoxythiazolo[5,4-b]pyridin-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(1.36 g, 3.46 mmol, 26.1% yield) to5-methoxythiazolo[5,4-b]pyridin-2-amine (0.34 g, 1.876 mmol, 14.17%yield). The mixture was taken directly to the next step without anyfurther purification. MS (LC/MS) R.T.=3.23; [M+H]⁺=392.1.

Step C:(2-(5-Methoxy-3a,7a-dihydrothiazolo[5,4-b]pyridin-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate

To(3-hydroxy-3-((3-(5-methoxythiazolo[5,4-b]pyridin-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(1.7 g, 3.46 mmol) in N,N-dimethylformamide (10 mL) was addedN,N′-diisopropylcarbodiimide (1.89 mL, 12.10 mmol). The reaction wasstirred at 70° C. for 2 hours. The mixture was cooled and then pouredinto water. The product was extracted with toluene and chloroform. Theorganic layers were combined, washed with brine, dried over sodiumsulfate, filtered and concentrated in vacuo to afford crude material.This solid material was triturated with ether. The solids were thenfiltered and dried to yield(2-(5-methoxy-3a,7a-dihydrothiazolo[5,4-b]pyridin-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate(700 mg, 1.94 mmol, 56.0% yield). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.98(1H, s), 7.86 (1 H, d, J=8.78 Hz), 6.81 (1H, d, J=8.42 Hz), 3.87 (3H,s), 3.83 (1H, s), 3.68-3.78 (1H, m), 3.31 (1H, s), 3.15-3.29 (1H, m),2.78-3.14 (4H, m), 2.26 (1H, br. s.), 2.04 (1H, br. s.), 1.63-1.89 (3H,m).

Step D:N-(5-Methoxythiazolo[5,4-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To(2-(5-methoxythiazolo[5,4-b]pyridin-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate(780 mg, 2.17 mmol) in acetone (10 mL) was added 3M HCl (10 mL, 329mmol). The reaction was stirred at room temperature for 2 hours.Chloroform and water were added and the aqueous layer was thenseparated. The aqueous layer was neutralized with sodium bicarbonate.The product was extracted with chloroform (2×). The organics werecombined, dried over sodium sulfate, filtered and concentrated in vacuoto afford racemicN-(5-methoxythiazolo[5,4-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(588 mg, 1.70 mmol, 78% yield) as a white powder.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.90 (1H, br. s.), 7.82-7.86 (1H, m),6.80 (1H, d, J=8.85 Hz), 3.84-3.89 (4H, m), 3.61 (1H, d, J=10.07 Hz),3.03 (2H, d, J=5.19 Hz), 2.73-2.86 (2H, m), 2.66 (2H, t, J=7.78 Hz),2.07 (1H, br. s.), 1.92 (1H, br. s.), 1.45-1.65 (3H, m). MS (LC/MS)R.T.=1.29; [M+H]⁺=346.1.

The enantiomers were separated using a Chiralpak AD-H (30×250 mm, 5 μm)column with a mobile phase consisting of 35% methanol (0.1% DEA) in CO₂.The wavelength was set at 300 nM. The separated peaks were concentratedin vacuo to yield white powders. The first peak off the column was(S)—N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(212 mg, 0.61 mmol, 36.1% yield). (2a; S-isomer): ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.89 (1H, br. s.), 7.84 (1H, d, J=8.85 Hz), 6.77-6.82(1H, m), 3.84-3.89 (4H, m), 3.61 (1H, d, J=10.07 Hz), 3.03 (2H, d,J=5.19 Hz), 2.74-2.86 (2H, m), 2.66 (2H, t, J=7.63 Hz), 2.06 (1H, br.s.), 1.92 (1H, br. s.), 1.44-1.65 (3H, m). MS (LC/MS) R.T.=1.47;[M+H]⁺=346.2. Optical rotation (3.57 mg/ml, DMSO)=−2.58°. The secondpeak was(R)—N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(242 mg, 0.70 mmol, 41.2% yield). (2b; R-isomer): ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.89 (1H, br. s.), 7.84 (1H, d, J=8.85 Hz), 6.79 (1H, d,J=8.55 Hz), 3.82-3.90 (4H, m), 3.61 (1H, d, J=10.07 Hz), 3.03 (2H, d,J=5.49 Hz), 2.74-2.86 (2H, m), 2.66 (2H, t, J=7.78 Hz), 2.06 (1H, br.s.), 1.92 (1H, br. s.), 1.42-1.67 (3H, m). MS (LC/MS) R.T.=1.30;[M+H]⁺=346.2. Optical rotation (3.29 mg/ml, DMSO)=+2.43°.

Example 3(2-(5H-1′-Azaspiro[oxazole-4,3′-bicyclo[2.2.2]octan]-2-ylamine)benzo[d]thiazol-6-yl)pyrrolidin-1-yl)methanone

Step A: tert-Butyl6-(pyrrolidine-1-carbonyl)benzo[d]thiazol-2-ylcarbamate

In a 250 ml flask was added2-(tert-butoxycarbonyl-amino)benzo[d]thiazole-6-carboxylic acid (1.0 g,3.4 mmol) and pyrrolidine (0.559 mL, 6.8 mmol) in tetrahydrofuran (50mL). To this solution was added EDC (1.3 g, 6.8 mmol),1-hydroxybenzotriaxole (1.041 g, 6.8 mmol) and Hunig's Base (2.37 mL,13.59 mmol). The reaction was stirred at 25° C. for 1 hour. The reactionwas then poured into water and dichloromethane. The water was extracted3 times with dichloromethane and the organic layers were combined andconcentrated. The residue was taken up in a small amount ofdichloromethane and precipitated out with diethyl ether/hexanes. Theflask was put in the freezer for 1 hour and filtered. The whiteprecipitate was collected to yield tert-butyl6-(pyrrolidine-1-carbonyl)benzo[d]thiazol-2-ylcarbamate (1.09 g, 3.14mmol, 92% yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.95 (s, 1H), 8.14(s, 1H), 7.61-7.77 (m, J=8.39, 1.98 Hz, 1H), 7.46-7.63 (m, 1H),3.39-3.63 (m, 4H), 1.74-2.00 (m, 4H), 1.45-1.62 (m, 9H). MS (LC/MS)R.T.=3.40; [M+H]⁺=363.1.

Step B: (2-Aminobenzo[d]thiazol-6-yl)(pyrrolidin-1-yl)methone

tert-Butyl 6-(pyrrolidine-1-carbonyl)benzo[d]thiazol-2-ylcarbamate (1.09g, 3.14 mmol) was dissolved in dichloromethane (10 mL) and TFA (3 mL,38.9 mmol) and the reaction was stirred at 25° C. overnight. Thereaction was poured into a reparatory funnel and carefully neutralizedwith sodium bicarbonate. The liquid was extracted 3 times withchloroform/methanol (4:1). The organic layers were concentrated to awhite residue and triturated in diethyl ether. The precipitate wascollected to yield (2-aminobenzo[d]thiazol-6-yl)(pyrrolidin-1-yl)methone(0.497 g, 2.0 mmol, 64%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.86 (d,J=1.51 Hz, 1H), 7.65 (s, 2H), 7.35-7.46 (m, 1H), 7.26-7.35 (m, 1H),3.41-3.57 (m, 4H), 1.64-1.97 (m, 4H). MS (LC/MS) R.T.=1.39;[M+H]⁺=248.1.

Step C:(2-(5H-1′-Azaspiro[oxazole-4,3′-bicyclo[2.2.2]octane]-2-ylamine)benzo[d]thiazol-6-yl)pyrrolidin-1-yl)methanone

(2-(5H-1′-Azaspiro[oxazole-4,3′-bicyclo[2.2.2]octane]-2-ylamine)benzo-[d]thiazol-6-yl)pyrrolidin-1-yl)methanonewas prepared by following the general procedures of Example 1, Steps A-Dand using (2-aminobenzo[d]thiazol-6-yl)(pyrrolidin-1-yl)methone (Example3, Step B) as the starting material. ¹H NMR (400 MHz, DMSO-d₆) δ ppm9.05 (br. s., 1H) 7.99 (d, J=1.76 Hz, 1H) 7.60 (d, J=8.31 Hz, 1H) 7.48(dd, J=8.31, 1.76 Hz, 1H) 3.90 (d, J=10.07 Hz, 1H) 3.65 (d, J=10.07 Hz,1H) 3.42-3.52 (m, 4H) 3.04 (s, 2H) 2.75-2.87 (m, 2H) 2.67 (t, J=7.81 Hz,2H) 2.08 (br. s., 1H) 1.76-1.98 (m, 5H) 1.41-1.65 (m, 3H). MS (LC/MS)R.T.=1.33; [M+H]⁺=412.2.

Example 4N-(5-Phenylthiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A:(3-Hydroxy-3-((3-(5-phenylthiazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate

To 5-phenylthiazol-2-amine (0.52 g, 2.9 mmol) in acetonitrile (6 mL) wasadded 1,1′-thiocarbonyldiimidazole (0.68 g, 3.8 mmol). The reactionmixture was stirred at 65° C. for 2 hours. The precipitate was filteredand washed with acetonitrile (2×20 mL) to yield intermediateN-(5-phenylthiazol-2-yl)-¹H-imidazole-1-carbothioamide. The intermediatewas taken up in N,N-dimethylformamide (30 mL) and treated with(3-(aminomethyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(0.5 g, 2.9 mmol). The reaction mixture was stirred for 5 hours at 65°C. The reaction was concentrated in vacuo and purified via silica gelchromatography (30-100% ethyl acetate/hexane). The product fractionswere combined and concentrated in vacuo to yield(3-hydroxy-3-((3-(5-phenylthiazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(0.85 g, 2.19 mmol, 74.4% yield) as a white powder. LC/MS confirmedproduct with loss of BH₃ in the LC/MS conditions: retention time 3.26(M+1−BH₃=375.33).

Step B:(2-(5-Phenylthiazol-2-ylamino)-4H-1′-ammoniospiro-[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate

To(3-hydroxy-3-((3-(5-phenylthiazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(0.8 g, 2.1 mmol) in N,N-dimethylformamide (20 mL) was addedN,N′-diisopropylcarbodiimide (1.12 mL, 7.2 mmol). The reaction mixturewas stirred at 70° C. for 4 hours. The reaction was concentrated invacuo and purified via silica gel chromatography (40-100% ethylacetate/hexane). The combined product fractions were concentrated invacuo to yield(2-(5-phenylthiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate(0.51 g, 1.44 mmol, 70% yield) as a white powder. LCMS-mass correspondsto BH₃ lost in the LC/MS conditions: retention time 2.46(M+1−BH₃=341.36).

Step C:N-(5-Phenylthiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To(2-(5-phenylthiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate(0.56 g, 1.58 mmol) in acetone (9 mL) was added 3 M HCl (3.95 mL, 11.86mmol). The reaction mixture was stirred at room temperature for 4 hoursand then neutralized with 1N sodium hydroxide. The product was extractedwith ethyl acetate (2×20 mL), followed by chloroform (2×20 mL). Theorganics were combined, dried with magnesium sulfate, filtered, andconcentrated in vacuo to afford a white powder. The crude product waspurified by reverse phase HPLC (Phenomenex Luna 30×100 mm; 220wavelength; gradient time 10 min; flow rate 40 ml/min; solvent A; 10%methanol-90% water-0.1% TFA, solvent B; 90% methanol-10% water-0.1%TFA). The fractions were combined, neutralized with 1N sodium hydroxideand extracted with ethyl acetate (2×30 mL) and chloroform (2×30 mL). Theorganics were combined, dried with magnesium sulfate, filtered andconcentrated in vacuo to yieldN-(5-phenylthiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.4 g, 1.175 mmol, 74.3% yield) as a white powder. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.63 (1H, br. s.), 7.71 (1H, s), 7.52 (2H, d, J=7.32 Hz),7.37 (2H, t, J=7.78 Hz), 7.25 (1H, t, J=7.32 Hz), 3.82 (1H, d, J=10.07Hz), 3.57 (1H, d, J=9.77 Hz), 3.02 (2H, d, J=4.27 Hz), 2.79 (2H, t,J=7.63 Hz), 2.66 (2H, t, J=7.63 Hz), 2.04 (1H, br. s.), 1.92-1.97 (1H,m), 1.44-1.65 (3H, m). MS (LC/MS) R.T.=1.52; [M+H]⁺=341.3.

The enantiomers were separated using a Chiralpak AS-H (30×250 mm, 5 μm)column with a mobile phase consisting of 30% methanol (0.1% DEA) in CO₂and UV monitored at 300 nm. The separated peaks were concentrated invacuo to yield white powders. The first peak off the column yielded 0.4g, 1.15 mmol, 32.7% (4a, S-isomer): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.69(s, 1H), 7.69-7.87 (m, 1H), 7.52-7.66 (m, J=10.99 Hz, 2H), 7.37-7.51 (m,2H), 7.21-7.38 (m, 2H), 3.52-4.00 (m, 2H), 2.98-3.23 (m, 2H), 2.78-2.94(m, 2H), 2.64-2.78 (m, 2H), 1.88-2.19 (m, J=60.43 Hz, 2H), 1.40-1.77 (m,3H). MS (LC/MS) R.T.=1.77; [M+H]⁺=341.1. The second peak yielded 0.4 g,1.15 mmol, 32.7%. (4b, R-isomer):L M.P. 187-9° C. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.64 (s, 1H), 7.62-7.84 (m, 1H), 7.44-7.61 (m, 2H),7.33-7.46 (m, 2H), 7.18-7.31 (m, 1H), 3.50-3.99 (m, 2H), 2.94-3.14 (m,2H), 2.74-2.91 (m, 2H), 2.61-2.72 (m, 2H), 2.05 (s, 1H), 1.82-2.00 (m,1H), 1.34-1.72 (m, 3H). MS (LC/MS) R.T.=1.78; [M+H]⁺=341.1.

Example 5N-(6-Methoxybenzo[d]thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amineStep A: N-(6-Methoxybenzo[d]thiazol-2-yl)-¹H-imidazole-1-carbothioamide

To 6-methoxybenzo[d]thiazol-2-amine (0.53 g, 2.94 mmol) in acetonitrile(20 mL) was added 1,1′-thiocarbonyldiimidazole (0.681 g, 3.82 mmol). Thereaction mixture was stirred at 65° C. for 24 hours. The precipitate wasfiltered and washed with acetonitrile (2×20 mL) to yield the product.The product was taken directly to the next step without any furtherpurification or characterization.

Step B:(3-Hydroxy-3-((3-(6-methoxybenzo[d]thiazol-2-yl)-thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate

To N-(6-methoxybenzo[d]thiazol-2-yl)-¹H-imidazole-1-carbothioamide (0.82g, 2.82 mmol) in N,N-dimethylformamide (20 mL) was added(3-(aminomethyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(0.48 g, 2.82 mmol). The reaction mixture was stirred at 65° C. for 6hours. The reaction was concentrated in vacuo and then purified bysilica gel chromatography (30%-100% ethyl acetate/hexanes). The purefractions were combined and concentrated to yield(3-hydroxy-3-((3-(6-methoxybenzo[d]thiazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(0.7 g, 1.78 mmol, 63.2% yield) as a white powder. LC/MS confirmedproduct as loss of BH₃ in the LC/MS conditions: retention time 3.11(M+1−BH₃=379.4).

Step C:(2-(6-Methoxybenzo[d]thiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate

To(3-hydroxy-3-((3-(6-methoxybenzo[d]thiazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(0.68 g, 1.73 mmol) in N,N-dimethylformamide (20 mL) was addedN,N′-diisopropylcarbodiimide (0.95 mL, 6.1 mmol). The reaction mixturewas stirred at 70° C. for 4 hours. The reaction was concentrated andpurified via silica gel chromatography (40-100% ethyl acetate/hexane).The product fractions were combined and concentrated in vacuo to yield(2-(6-methoxybenzo[d]thiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate(0.35 g, 0.98 mmol, 56.4% yield) as a white powder. LC/MS MH⁺−BH₃=345.2.

Step D:N-(6-Methoxybenzo[d]thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To(2-(6-methoxybenzo[d]thiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate(0.33 g, 0.921 mmol) in acetone (9 mL) was added 3 M HCl (2.30 mL, 6.91mmol). The reaction was stirred at room temperature for 4 hours and thenneutralized with 1N sodium hydroxide. The product was extracted withethyl acetate (2×20 mL), followed by chloroform (2×20 mL). The organicswere combined, dried with magnesium sulfate, filtered, and concentratedin vacuo to afford a white powder. The crude product was purified byreverse phase HPLC (Phenomenex Luna 30×100 mm; 220 wavelength; gradienttime 10 min; flow rate 40 ml/min; solvent A; 10% methanol-90% water-0.1%TFA, solvent B; 90% methanol-10% water-0.1% TFA). The fractions werecombined, neutralized with 1N sodium hydroxide and extracted with ethylacetate (2×30 mL). The organics were combined, dried with magnesiumsulfate, filtered and concentrated in vacuo to yieldN-(6-methoxybenzo[d]thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.25 g, 0.73 mmol, 79% yield) as a white powder. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.88 (1H, d, J=1.22 Hz), 7.48-7.52 (1H, m), 7.40 (1H, d,J=2.75 Hz), 6.92 (1H, dd, J=8.70, 2.59 Hz), 3.87 (1H, d, J=9.77 Hz),3.77 (3H, s), 3.61 (1H, d, J=9.77 Hz), 3.03 (2H, s), 2.75-2.86 (2H, m),2.67 (2H, t, J=7.78 Hz), 2.06 (1H, br. s.), 1.91 (1H, br. s.), 1.41-1.65(3H, m). MS (LC/MS) R.T.=1.44; [M+H]⁺=345.3.

The enantiomers were separated using a Chiralpak AD-H (30×250 mm, 5 μm)column with a mobile phase consisting of 23% methanol (0.1% DEA) in CO₂and UV monitored at 220 nm. The separated peaks were concentrated invacuo to yield white powders. The first peak off the column yielded205.5 mg, 0.60 mmol, 34.1%. (5a, S-isomer): ¹H NMR (400 MHz, DMSO-d₆) δppm 8.88 (1H, br. s.), 7.50 (1H, d, J=8.81 Hz), 7.40 (1H, d, J=2.52 Hz),6.92 (1H, dd, J=8.81, 2.77 Hz), 3.87 (1H, d, J=9.82 Hz), 3.77 (3H, s),3.58-3.65 (1H, m), 3.02 (2H, s), 2.74-2.86 (2H, m), 2.66 (2H, t, J=7.68Hz), 2.03-2.08 (1H, m), 1.91 (1H, br. s.), 1.39-1.65 (3H, m). MS (LC/MS)R.T.=1.40; [M+H]⁺=345.2. The second peak yielded 206.9 mg, 0.6 mmol,34%. (5b, R-isomer): ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.88 (1H, br. s.),7.50 (1H, d, J=8.56 Hz), 7.40 (1H, d, J=2.52 Hz), 6.93 (1H, dd, J=8.81,2.52 Hz), 3.87 (1H, d, J=10.07 Hz), 3.77 (3H, s), 3.62 (1H, d, J=10.07Hz), 3.02 (2H, s), 2.75-2.86 (2H, m), 2.67 (2H, t, J=7.68 Hz), 2.04-2.09(1H, m), 1.92 (1H, br. s.), 1.42-1.66 (3H, m). MS (LC/MS) R.T.=1.70;[M+H]⁺=345.1.

Example 6N-(4-Methylbenzo[d]thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: N-(4-Methylbenzo[d]thiazol-2-yl)-¹H-imidazole-1-carbothioamide

To 4-methylbenzo[d]thiazol-2-amine (1.1 g, 6.7 mmol) in acetonitrile (30mL) was added 1,1′-thiocarbonyldiimidazole (1.552 g, 8.71 mmol). Thereaction mixture was stirred at 50° C. for 18 hours. The reaction wascooled to room temperature and the precipitate was filtered and washedwith acetonitrile (2×50 mL). The yellow powder was dried in a vacuumoven (50° C.) for 1 hour to yieldN-(4-methylbenzo[d]thiazol-2-yl)-¹H-imidazole-1-carbothioamide (900 mg,3.28 mmol, 49% yield) and then used in the next step without any furtherpurification or characterization.

Step B:(3-Hydroxy-3-((3-(4-methylbenzo[d]thiazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate

To N-(4-methylbenzo[d]thiazol-2-yl)-¹H-imidazole-1-carbothioamide (0.71g, 2.59 mmol) in N,N-dimethylformamide (20 mL) was added(3-(aminomethyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(0.44 g, 2.59 mmol). The reaction mixture was stirred at 70° C. for 4hours. The reaction was concentrated and purified via silica gelchromatography (40-100% ethyl acetate/hexanes). The product fractionswere concentrated in vacuo to yield(3-hydroxy-3-((3-(4-methylbenzo[d]thiazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(0.65 g, 1.73 mmol, 66.7% yield) as a white powder. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 11.93 (1H, s), 7.74 (1H, d, J=7.63 Hz), 7.22-7.26 (1H,m), 7.19 (1H, t, J=7.63 Hz), 3.75-3.93 (2H, m), 2.72-2.95 (6H, m), 2.56(3H, s), 2.03-2.14 (1H, m), 1.95 (1H, br. s.), 1.78-1.87 (1H, m), 1.73(1H, ddd, J=13.81, 9.23, 5.04 Hz), 1.56 (1H, td, J=9.99, 7.78 Hz), 1.38(2H, br. s.). (LC/MS) R.T.=3.70; [M+H]⁺=375.2.

Step C:(2-(4-Methylbenzo[d]thiazol-2-ylamino)-4H-1′-ammonio-spiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate

To(3-hydroxy-3-((3-(4-methylbenzo[d]thiazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(0.62 g, 1.65 mmol) in N,N-dimethylformamide (20 mL) was addedN,N′-diisopropylcarbodiimide (0.33 mL, 2.14 mmol). The reaction mixturewas stirred at 70° C. for 4 hours. The reaction was concentrated andpurified via silica gel chromatography (40-100% ethyl acetate/hexanes).The product fractions were concentrated in vacuo to yield(2-(4-methylbenzo[d]thiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate(0.4 g, 1.17 mmol, 70.9% yield) as a white powder. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.90 (s, 1H), 7.61 (d, J=7.63 Hz, 1H), 7.13-7.17 (m, 1H),7.09 (t, J=7.48 Hz, 1H), 3.90 (d, J=10.38 Hz, 1H), 3.77 (d, J=10.38 Hz,1H), 3.32 (s, 3H), 3.30 (d, J=1.53 Hz, 1H), 3.13-3.20 (m, 2H), 3.00-3.09(m, 1H), 2.85-2.94 (m, 4H), 2.57 (s, 4H), 2.28 (s, 1H), 2.06 (s, 1H),1.75-1.83 (m, 4H), 1.45 (s, 1H). (LC/MS) R.T.=2.73; [M+H]⁺=343.2.

Step D:N-(4-Methylbenzo[d]thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To(2-(4-methylbenzo[d]thiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate(0.38 g, 1.11 mmol) in acetone (9 mL) was added 3 M HCl (2.78 mL, 8.33mmol). The reaction mixture was stirred at room temperature for 4 hours.Ethyl acetate was added and the aqueous layer was collected andneutralized with 1N sodium hydroxide. The product was extracted withethyl acetate (2×40 mL). The organics were combined, dried withmagnesium sulfate, filtered and concentrated in vacuo to affordN-(4-methylbenzo[d]thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.195 g, 0.594 mmol, 53.5% yield) as a white powder. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.84 (s, 1H), 7.60 (d, J=7.32 Hz, 1H), 7.13-7.17 (m, 1H),7.08 (t, J=7.63 Hz, 1H), 3.92 (d, J=10.07 Hz, 1H), 3.66 (d, J=9.77 Hz,1H), 3.04 (s, 2H), 2.76-2.85 (m, 2H), 2.68 (t, J=7.48 Hz, 2H), 2.56 (s,3H), 2.09 (s, 1H), 1.93 (s, 1H), 1.61 (d, J=3.05 Hz, 1H), 1.60 (s, 1H),1.50 (dd, J=7.17, 2.59 Hz, 1H). (LC/MS) R.T.=1.76; [M+H]⁺=329.2.

The enantiomers were separated using a Chiralcel OJ-H (30×250 mm, 5 μm)column with a mobile phase consisting of 30% methanol (0.1% DEA) in CO₂and UV monitored at 300 nm. The separated peaks were concentrated invacuo to yield white powders. The first peak off the column yielded 0.07g, 0.21 mmol, 38.9%. (6a, S-isomer): ¹H NMR (500 MHz, DMSO-d₆) δ ppm8.83 (br. s., 1H) 7.59 (d, J=7.63 Hz, 1H) 7.11-7.18 (m, 1H) 7.08 (t,J=7.63 Hz, 1H) 3.92 (d, J=10.38 Hz, 1H) 3.66 (d, J=9.77 Hz, 1H) 3.04 (s,2H) 2.73-2.89 (m, 2H) 2.61-2.72 (m, 2H) 2.56 (s, 3H) 2.09 (br. s., 1H)1.93 (br. s., 1H) 1.43-1.71 (m, 3H). MS (LC/MS) R.T.=1.75; [M+H]⁺=329.1.The second peak yielded 0.07 g, 0.21 mmol, 38.1%. (6b, R-isomer): ¹H NMR(500 MHz, DMSO-d₆) δ ppm 8.84 (br. s., 1H) 7.59 (d, J=7.63 Hz, 1H) 7.15(d, J=7.20 Hz, 1H) 7.08 (t, J=7.48 Hz, 1H) 3.92 (d, J=9.77 Hz, 1H) 3.66(d, J=10.07 Hz, 1H) 3.00-3.09 (m, 2H) 2.73-2.87 (m, 2H) 2.62-2.72 (m,2H) 2.56 (s, 3H) 2.05-2.12 (m, 1H) 1.93 (br. s., 1H) 1.56-1.67 (m, 2H)1.45-1.55 (m, 1H). MS (LC/MS) R.T.=1.75; [M+H]⁺=329.1.

Example 7N-(4-Chlorobenzo[d]thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: N-(4-Chlorobenzo[d]thiazol-2-yl)-¹H-imidazole-1-carbothioamide

To 4-chlorobenzo[d]thiazol-2-amine (1.12 g, 6.07 mmol) in acetonitrile(30 mL) was added 1,1′-thiocarbonyldiimidazole (1.405 g, 7.89 mmol). Thereaction mixture was stirred at 50° C. for 18 hours. The reaction wascooled to room temperature and the precipitate was filtered and washedwith acetonitrile (2×50 mL). The yellow powder was dried in a vacuumoven (40° C.) for 1 hour to yieldN-(4-chlorobenzo[d]thiazol-2-yl)-¹H-imidazole-1-carbothioamide (0.33 g,1.12 mmol, 18.5% yield) and then used in the next step without anyfurther purification or characterization.

Step B:(3-((3-(4-Chlorobenzo[d]thiazol-2-yl)thioureido)methyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate

To N-(4-chlorobenzo[d]thiazol-2-yl)-¹H-imidazole-1-carbothioamide (0.3g, 1.018 mmol) in N,N-dimethylformamide (20 mL) was added(3-(aminomethyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(0.173 g, 1.018 mmol). The reaction mixture was stirred at 70° C. for 4hours. The reaction was concentrated and purified via silica gelchromatography (60-100% ethyl acetate/hexanes). The product fractionswere concentrated in vacuo to yield(3-((3-(4-chlorobenzo[d]thiazol-2-yl)thioureido)methyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(0.25 g, 0.63 mmol, 61.9% yield) as a white powder. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 12.19 (s, 1H) 9.72 (br. s., 1H) 7.93 (d, J=7.93 Hz, 1H)7.51 (d, J=7.93 Hz, 1H) 7.26-7.32 (m, 1H) 5.32 (s, 1H) 3.88 (dd,J=13.73, 4.88 Hz, 1H) 3.75 (dd, J=13.73, 4.88 Hz, 1H) 2.73-2.95 (m, 6H)2.08 (br. s., 1H) 1.96 (br. s., 1H) 1.79-1.89 (m, 1H) 1.68-1.78 (m, 1H)1.52-1.61 (m, 1H) 1.39 (br. s., 3H).

Step C:(2-(4-Chlorobenzo[d]thiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate

To(3-((3-(4-chlorobenzo[d]thiazol-2-yl)thioureido)methyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(0.23 g, 0.58 mmol) in N,N-dimethylformamide (20 mL) was addedN,N′-diisopropylcarbodiimide (0.117 mL, 0.75 mmol). The reaction mixturewas stirred at 70° C. for 4 hours. The reaction was concentrated andpurified via silica gel chromatography (40-100% ethyl acetate/hexanes).The product fractions were concentrated in vacuo to yield(2-(4-chlorobenzo[d]thiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate(0.1 g, 0.27 mmol, 47.6% yield) as a white powder. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.95 (s, 1H) 7.79 (d, J=7.93 Hz, 1H) 7.42 (d, J=7.63 Hz,1H) 7.18 (t, J=7.93 Hz, 1H) 3.92 (d, J=10.38 Hz, 1H) 3.77 (d, J=10.38Hz, 1H) 3.26-3.38 (m, 1H) 3.19 (dd, J=15.26, 1.53 Hz, 1H) 3.01-3.11 (m,1H) 2.81-3.00 (m, 3H) 2.31 (br. s., 1H) 2.03-2.15 (m, 1H) 1.70-1.89 (m,3H) 1.45 (br. s., 3H).

Step D:N-(4-Chlorobenzo[d]thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To(2-(4-chlorobenzo[d]thiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate(0.08 g, 0.221 mmol) in acetone (9 mL) was added 3 M HCl (0.551 mL,1.654 mmol). The reaction mixture was stirred at room temperature for 4hours. Ethyl acetate was added and the aqueous layer was collected andneutralized with 1N sodium hydroxide. The product was extracted withethyl acetate (2×40 mL). The organics were combined, dried withmagnesium sulfate, filtered and concentrated in vacuo to affordN-(4-chlorobenzo[d]thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.05 g, 0.14 mmol, 65.0% yield) as a white powder. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.90 (br. s., 1H) 7.77 (dd, J=7.78, 1.07 Hz, 1H) 7.41(dd, J=7.78, 1.07 Hz, 1H) 7.17 (t, J=7.78 Hz, 1H) 3.94 (d, J=10.07 Hz,1H) 3.67 (d, J=10.07 Hz, 1H) 3.00-3.11 (m, 2H) 2.76-2.88 (m, 2H) 2.68(t, J=7.63 Hz, 2H) 2.11 (br. s., 1H) 1.91-2.00 (m, 1H) 1.47-1.67 (m,3H). MS (LC/MS) R.T.=2.11; [M+H]⁺=349.1.

The enantiomers were separated using a Chiralcel OJ-H (30×250 mm, 5 μm)column with a mobile phase consisting of 30% methanol (0.1% DEA) in CO₂.The wavelength was set at 220 nM. The separated peaks were concentratedin vacuo to yield white powders. The first peak off the column was(S)—N-(4-chlorobenzo[d]thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.11 g, 0.30 mmol, 34.8% yield). (7a, S-isomer): ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.90 (br. s., 1H) 7.77 (d, J=7.32 Hz, 1H) 7.41 (d, J=7.93Hz, 1H) 7.17 (t, J=7.93 Hz, 1H) 3.94 (d, J=10.07 Hz, 1H) 3.67 (d,J=10.07 Hz, 1H) 3.00-3.11 (m, 2H) 2.76-2.90 (m, 2H) 2.68 (t, J=7.78 Hz,2H) 2.11 (br. s., 1H) 1.91-2.01 (m, 1H) 1.47-1.68 (m, 3H). MS (LC/MS)R.T.=2.06; [M+H]⁺=349.1. The second peak was(R)—N-(4-chlorobenzo[d]thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.11 g, 0.30 mmol, 35.2% yield). (7b, R-isomer): ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.89 (br. s., 1H) 7.77 (d, J=7.93 Hz, 1H) 7.40 (d, J=7.93Hz, 1H) 7.16 (t, J=7.93 Hz, 1H) 3.94 (d, J=10.07 Hz, 1H) 3.67 (d,J=10.07 Hz, 1H) 2.99-3.11 (m, 2H) 2.74-2.88 (m, 2H) 2.68 (t, J=7.78 Hz,2H) 2.11 (br. s., 1H) 1.90-2.01 (m, 1H) 1.44-1.68 (m, 3H). MS (LC/MS)R.T.=2.07; [M+H]⁺=349.1.

Example 8N—(¹H-Benzo[d]imidazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: N—(¹H-Benzo[d]imidazol-2-yl)-¹H-imidazole-1-carbothioamide

To ¹H-benzo[d]imidazol-2-amine (1.28 g, 9.61 mmol) in acetonitrile (30mL) was added 1,1′-thiocarbonyldiimidazole (2.227 g, 12.5 mmol). Thereaction mixture was stirred at 50° C. for 18 hours. The reaction wascooled to room temperature and the precipitate was filtered and washedwith acetonitrile (2×50 mL). The yellow powder was dried in a vacuumoven (40° C.) for 1 hour to yieldN—(¹H-benzo[d]imidazol-2-yl)-¹H-imidazole-1-carbothioamide (1.8 g, 7.4mmol, 77% yield) and then used in the next step without any furtherpurification or characterization.

Step B:(3-((3-¹H-Benzo[d]imidazol-2-ylthioureido)methyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate

To N—(¹H-benzo[d]imidazol-2-yl)-¹H-imidazole-1-carbothioamide (1.07 g,4.4 mmol) in N,N-dimethylformamide (20 mL) was added(3-(aminomethyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(0.748 g, 4.4 mmol). The reaction mixture was stirred at 70° C. for 4hours. The reaction was concentrated and purified via silica gelchromatography (60-100% ethyl acetate/hexane). The product fractionswere concentrated in vacuo to yield(3-((3-¹H-benzo[d]imidazol-2-ylthioureido)methyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(1.28 g, 3.71 mmol, 84% yield) as a white powder. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 11.41 (s, 1H), 11.16 (s, 1H), 7.43 (d, J=3.05 Hz, 3H),7.13 (ddd, J=9.46, 3.81, 3.51 Hz, 3H), 5.36 (s, 1H), 4.01-4.07 (m, 3H),3.79 (dd, J=13.28, 4.12 Hz, 1H), 2.83-2.92 (m, 6H), 2.71 (d, J=14.04 Hz,2H), 2.04-2.13 (m, 2H), 1.89-1.94 (m, 3H), 1.74 (td, J=9.46, 5.49 Hz,2H), 1.51-1.59 (m, 2H), 1.38 (s, 2H), 1.31 (s, 1H).

LC/MS confirmed product as loss of BH₃ in the LC/MS conditions:retention time 2.75 (M+1−BH₃=332.2).

Step C:(2-(¹H-Benzo[d]imidazol-2-ylamino)-4H-1′-ammoniospiro-[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate

To(3-((3-¹H-benzo[d]imidazol-2-ylthioureido)methyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(1.0 g, 2.9 mmol) in N,N-dimethylformamide (20 mL) was addedN,N′-diisopropylcarbodiimide (0.587 mL, 3.77 mmol). The reaction mixturewas stirred at 70° C. for 4 hours. The reaction was concentrated andpurified via silica gel chromatography (40-100% ethyl acetate/hexane).The product fractions were concentrated in vacuo to yield(2-(¹H-benzo[d]imidazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate(0.81 g, 2.6 mmol, 90% yield) as a white powder. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 7.29 (s, 1H), 6.99-7.05 (m, 2H), 3.90 (t, J=9.77 Hz, 1H),3.75 (d, J=10.38 Hz, 1H), 3.26-3.35 (m, 1H), 3.13 (dd, J=14.95, 1.53 Hz,1H), 2.98-3.06 (m, 1H), 2.84-2.92 (m, 3H), 2.22 (s, 1H), 1.98-2.05 (m,1H), 1.72-1.82 (m, 3H), 1.45 (s, 1H). LC/MS confirmed product as loss ofBH₃ in the LC/MS conditions: retention time 2.29 (M+1−BH₃=298.2).

Step D:N—(¹H-Benzo[d]imidazol-2-yl)-4H-1′-azaspiro-[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To(2-(¹H-benzo[d]imidazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate(0.77 g, 2.5 mmol) in acetone (9 mL) was added 3 M HCl (6.2 mL, 18.6mmol). The reaction was stirred at room temperature for 4 hours. Ethylacetate was added and the aqueous layer was collected and neutralizedwith 1N sodium hydroxide. The product was extracted with ethyl acetate(2×40 mL). The organics were combined, dried with magnesium sulfate,filtered and concentrated in vacuo to affordN—(¹H-benzo[d]imidazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.5 g, 1.68 mmol, 68% yield) as a white powder. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 11.45 (s, 1H), 9.20 (s, 1H), 7.32 (s, 1H), 7.00 (dd,J=5.65, 2.90 Hz, 4H), 3.91 (d, J=10.07 Hz, 2H), 3.64 (d, J=10.07 Hz,2H), 2.98-3.05 (m, 4H), 2.73-2.82 (m, 4H), 2.67 (t, J=7.63 Hz, 4H), 2.03(d, J=2.75 Hz, 2H), 1.85-1.92 (m, 2H), 1.54-1.63 (m, 4H), 1.44-1.51 (m,2H). MS (LC/MS) R.T.=1.30; [M+H]⁺=298.2.

The enantiomers were separated using a Chiralpak AS-H (30×250 mm, 5 μm)column with a mobile phase consisting of 30% methanol (0.1% DEA) in CO₂and UV monitored at 330 nm. The separated peaks were concentrated invacuo to yield white powders. The first peak off the column yielded 0.11g, 0.36 mmol, 33.0%. (8a; R-isomer): M.P. 255° C. (dec). ¹H NMR (500MHz, DMSO-d₆) δ ppm 11.43 (br. s., 1H) 9.16 (br. s., 1H) 7.14-7.53 (m,2H) 6.82-7.09 (m, 2H) 3.91 (d, J=9.77 Hz, 1 H) 3.64 (d, J=10.07 Hz, 1H)2.96-3.09 (m, 2H) 2.71-2.87 (m, 2H) 2.62-2.73 (m, 2H) 2.01-2.08 (m, 1H)1.81-1.97 (m, 1H) 1.54-1.66 (m, 2H) 1.40-1.53 (m, 1H). MS (LC/MS)R.T.=1.26; [M+H]⁺=298.2. The second peak yielded 0.11 g, 0.36 mmol,33.0%. (8b; S-isomer): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.43 (br. s.,1H) 9.20 (br. s., 1H) 7.10-7.60 (m, 2H) 6.83-7.11 (m, 2H) 3.91 (d,J=9.77 Hz, 1H) 3.64 (d, J=9.77 Hz, 1H) 2.94-3.16 (m, 2H) 2.71-2.86 (m,2H) 2.59-2.72 (m, 2H) 1.97-2.09 (m, 1H) 1.81-1.95 (m, 1H) 1.53-1.71 (m,2H) 1.41-1.53 (m, 1H). MS (LC/MS) R.T.=1.28; [M+H]⁺=298.2.

Example 9N-(6-Chlorobenzo[d]thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: N-(6-Chlorobenzo[d]thiazol-2-yl)-¹H-imidazole-1-carbothioamide

To 6-chlorobenzo[d]thiazol-2-amine (1.14 g, 6.17 mmol) in acetonitrile(30 mL) was added 1,1′-thiocarbonyldiimidazole (1.43 g, 8 mmol). Thereaction was stirred at 50° C. for 18 hours. The reaction was cooled toroom temperature and the precipitate was filtered and washed withacetonitrile (2×50 mL). The yellow powder was dried in a vacuum oven(40° C.) for 1 hour to yieldN-(6-chlorobenzo[d]thiazol-2-yl)-¹H-imidazole-1-carbothioamide (1.16 g,3.9 mmol, 64% yield) and then used in the next step without any furtherpurification or characterization.

Step B:(3-((3-(6-Chlorobenzo[d]thiazol-2-yl)thioureido)methyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate

To N-(6-chlorobenzo[d]thiazol-2-yl)-¹H-imidazole-1-carbothioamide (0.86g, 2.9 mmol) in N,N-dimethylformamide (20 mL) was added(3-(aminomethyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(0.5 g, 2.9 mmol). The reaction was stirred at 70° C. for 4 hours. Thereaction was concentrated and purified via silica gel chromatography(60-100% ethyl acetate/hexanes). The product fractions were concentratedin vacuo to yield(3-((3-(6-chlorobenzo[d]thiazol-2-yl)thioureido)methyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(0.4 g, 1.01 mmol, 34.6% yield) as a white powder. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 11.92 (br. s., 1H) 9.89 (br. s., 1H) 8.08 (br. s., 1H)7.62 (br. s., 1H) 7.40-7.50 (m, 1H) 5.40 (br. s., 1H) 3.88 (d, J=10.20Hz, 1H) 3.76 (d, J=10.20 Hz, 1H) 2.67-3.02 (m, 6H) 2.08 (br. s., 1H)1.80-1.95 (m, 2H) 1.73 (br. s., 1H) 1.01-1.63 (m, 4H). MS (LC/MS)R.T.=3.87; [M+H]⁺=395.1.

Step C:(2-(6-Chlorobenzo[d]thiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate

To(3-((3-(6-chlorobenzo[d]thiazol-2-yl)thioureido)methyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(0.37 g, 0.93 mmol) in N,N-dimethylformamide (20 mL) was addedN,N′-diisopropylcarbodiimide (0.19 mL, 1.2 mmol). The reaction wasstirred at 70° C. for 4 hours. The reaction was concentrated andpurified via silica gel chromatography (40-100% ethyl acetate/hexane).The product fractions were concentrated in vacuo to yield(2-(6-chlorobenzo[d]thiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate(0.12 g, 0.33 mmol, 35.5% yield) as a white powder. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 9.10 (br. s., 1H) 7.95 (d, J=2.14 Hz, 1H) 7.60 (d, J=8.55Hz, 1H) 7.36 (dd, J=8.55, 2.14 Hz, 1H) 3.88 (d, J=10.38 Hz, 1H) 3.76 (d,J=10.38 Hz, 1H) 3.26-3.37 (m, 1H) 3.17 (dd, J=14.95, 1.83 Hz, 1H)3.00-3.11 (m, 1H) 2.80-2.97 (m, 3H) 2.28 (br. s., 1H) 2.00-2.11 (m, 1H)1.69-1.88 (m, 3H) 1.46 (br. s., 3H). LC/MS: retention time 2.94(M+1−BH₃=349.1).

Step D:N-(6-Chlorobenzo[d]thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To(2-(6-chlorobenzo[d]thiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate(0.1 g, 0.28 mmol) in acetone (9 mL) was added 3 M HCl (0.69 mL, 2.07mmol). The reaction was stirred at room temperature for 4 hours. Ethylacetate was added and the aqueous layer was collected and neutralizedwith 1N sodium hydroxide. The product was extracted with ethyl acetate(2×40 mL). The organics were combined, dried with magnesium sulfate,filtered and concentrated in vacuo to affordN-(6-chlorobenzo[d]thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.06 g, 0.17 mmol, 62.4% yield) as a white powder. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 9.03 (br. s., 1H) 7.93 (d, J=2.14 Hz, 1H) 7.58 (d, J=8.55Hz, 1H) 7.35 (dd, J=8.55, 2.14 Hz, 1H) 3.90 (d, J=10.07 Hz, 1H) 3.65 (d,J=10.07 Hz, 1H) 2.99-3.11 (m, 2H) 2.73-2.89 (m, 2H) 2.67 (t, J=7.63 Hz,2H) 2.08 (br. s., 1H) 1.82-1.99 (m, 1H) 1.43-1.67 (m, 3H). MS (LC/MS)R.T.=2.07; [M+H]⁺=349.1.

The enantiomers were separated using a Chiralpak AS-H (30×250 mm, 5 μm)column with a mobile phase consisting of 30% methanol (0.1% DEA) in CO₂and UV monitored at 220 nm. The separated peaks were concentrated invacuo to yield white powders. The first peak off the column yielded0.034 g, 0.10 mmol, 36.2%. (9a; S-isomer): ¹H NMR (500 MHz, DMSO-d₆) δppm 9.02 (br. s., 1H) 7.93 (d, J=2.14 Hz, 1H) 7.58 (d, J=8.55 Hz, 1H)7.35 (dd, J=8.55, 2.14 Hz, 1H) 3.90 (d, J=10.07 Hz, 1H) 3.65 (d, J=10.07Hz, 1H) 2.97-3.11 (m, 2H) 2.73-2.89 (m, 2H) 2.67 (t, J=7.48 Hz, 2H) 2.08(br. s., 1H) 1.93 (br. s., 1H) 1.43-1.69 (m, 3H). MS (LC/MS) R.T.=2.05;[M+H]⁺=349.1. Optical rotation=+4.00°. The second peak yielded 0.037 g,0.10 mmol, 39.4%. (9b; R-isomer): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.02(br. s., 1H) 7.93 (d, J=2.14 Hz, 1H) 7.58 (d, J=8.55 Hz, 1H) 7.35 (dd,J=8.55, 2.44 Hz, 1H) 3.90 (d, J=10.07 Hz, 1H) 3.65 (d, J=10.07 Hz, 1H)2.93-3.13 (m, 2H) 2.72-2.91 (m, 2H) 2.62-2.73 (m, 2H) 2.08 (br. s., 1H)1.93 (d, J=1.22 Hz, 1H) 1.44-1.68 (m, 3H). MS (LC/MS) R.T.=2.04;[M+H]⁺=349.1. Optical rotation=−3.74°.

Example 10N-(1-Methyl-¹H-benzo[d]imidazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A:N-(1-Methyl-¹H-benzo[d]imidazol-2-yl)-¹H-imidazole-1-carbothioamide

To 1-methyl-¹H-benzo[d]imidazol-2-amine (1.28 g, 8.7 mmol) inacetonitrile (30 mL) was added 1,1′-thiocarbonyldiimidazole (2.015 g,11.31 mmol). The reaction was stirred at 50° C. for 18 hours. Thereaction was cooled to room temperature and the precipitate was filteredand washed with acetonitrile (2×50 mL). The yellow powder was dried in avacuum oven (40° C.) for 1 hour to yieldN-(1-methyl-¹H-benzo[d]imidazol-2-yl)-¹H-imidazole-1-carbothioamide (1.6g, 6.22 mmol, 71.5% yield) and then used in the next step without anyfurther purification or characterization.

Step B:(3-Hydroxy-3-((3-(1-methyl-¹H-benzo[d]imidazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate

To N-(1-methyl-¹H-benzo[d]imidazol-2-yl)-¹H-imidazole-1-carbothioamide(1.04 g, 4.04 mmol) in N,N-dimethylformamide (20 mL) was added(3-(aminomethyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(0.687 g, 4.04 mmol). The reaction was stirred at 70° C. for 4 hours.The reaction was concentrated and purified via silica gel chromatography(60-100% ethyl acetate/hexane). The product fractions were concentratedin vacuo to yield(3-hydroxy-3-((3-(1-methyl-¹H-benzo[d]imidazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(1.28 g, 3.56 mmol, 88% yield) as a white powder. LC/MS confirmedproduct as loss of BH₃ in the LC/MS conditions: retention time 3.01(M+1−BH₃=346.2).

Step C:(2-(1-Methyl-¹H-benzo[d]imidazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate

To(3-hydroxy-3-((3-(1-methyl-¹H-benzo[d]imidazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(1.19 g, 3.31 mmol) in N,N-dimethylformamide (20 mL) was addedN,N′-diisopropylcarbodiimide (1.55 mL, 9.9 mmol). The reaction wasstirred at 70° C. for 4 hours. The reaction was concentrated andpurified via silica gel chromatography (40-100% ethyl acetate/hexane).The product fractions were concentrated in vacuo to yield(2-(1-methyl-¹H-benzo[d]imidazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate(0.94 g, 2.9 mmol, 87% yield) as a white powder. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 9.36 (br. s., 1H) 7.34-7.44 (m, 1H) 7.26-7.34 (m, 1H)7.00-7.12 (m, 2H) 3.90 (d, J=10.32 Hz, 1H) 3.77 (d, J=10.32 Hz, 1H) 3.57(s, 3H) 3.28 (dd, J=14.86, 2.27 Hz, 1H) 3.13 (dd, J=14.86, 1.51 Hz, 1H)2.95-3.08 (m, 1H) 2.75-2.95 (m, 3H) 2.22 (br. s., 1H) 1.96-2.11 (m, 1H)1.67-1.89 (m, 3H) 1.43 (br. s., 3H). LC/MS: retention time 2.37(M+1-BH₃=312.2).

Step D:N-(1-Methyl-¹H-benzo[d]imidazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To(2-(1-methyl-¹H-benzo[d]imidazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate(0.92 g, 2.8 mmol) in acetone (9 mL) was added 3 M HCl (7.1 mL, 21.2mmol). The reaction was stirred at room temperature for 4 hours. Ethylacetate was added and the aqueous layer was collected and neutralizedwith 1N sodium hydroxide. The product was extracted with ethyl acetate(2×40 mL). The organics were combined, dried with magnesium sulfate,filtered, and concentrated in vacuo to affordN-(1-methyl-¹H-benzo[d]imidazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.84 g, 2.7 mmol, 95% yield) as a white powder. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 9.24-9.39 (m, 1H) 7.33-7.42 (m, 1H) 7.25-7.33 (m, 1H)6.99-7.10 (m, 2H) 3.92 (d, J=10.07 Hz, 1H) 3.66 (d, J=10.07 Hz, 1H) 3.57(s, 3H) 2.97-3.08 (m, 2H) 2.78 (t, J=7.81 Hz, 2H) 2.67 (t, J=7.81 Hz,2H) 2.01-2.09 (m, 1H) 1.80-1.96 (m, 1H) 1.40-1.66 (m, 3H). MS (LC/MS)R.T.=1.49; [M+H]⁺=312.2.

The enantiomers were separated using a Chiralcel OJ-H (30×250 mm, 5 μm)column with a mobile phase consisting of 22% methanol (0.1% DEA) in CO₂and UV monitored at 300 nm. The separated peaks were concentrated invacuo to yield white powders. The first peak off the column yielded0.065 g, 0.205 mmol, 39.8%. (10a, R-isomer): ¹H NMR (500 MHz, DMSO-d₆) δppm 9.31 (br. s., 1H) 7.35-7.45 (m, 1H) 7.26-7.34 (m, 1H) 7.00-7.15 (m,2H) 3.93 (d, J=10.10 Hz, 1H) 3.67 (d, J=10.10 Hz, 1H) 3.59 (s, 3H)2.93-3.13 (m, 2H) 2.74-2.89 (m, 2H) 2.61-2.74 (m, 2H) 2.05 (br. s., 1H)1.91 (br. s., 1H) 1.38-1.68 (m, 3H). MS (LC/MS) R.T.=1.37; [M+H]⁺=312.2.Optical rotation=−16.02°. The second peak yielded 0.06 g, 0.19 mmol,36.8%. (10b; S-isomer): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.31 (br. s.,1H) 7.33-7.43 (m, 1H) 7.25-7.33 (m, 1H) 6.93-7.11 (m, 2H) 3.93 (dd,J=9.92, 3.20 Hz, 1H) 3.67 (dd, J=9.92, 3.20 Hz, 1H) 3.58 (s, 3H)2.94-3.13 (m, 2H) 2.74-2.85 (m, 2H) 2.59-2.72 (m, 2H) 2.04 (br. s., 1H)1.90 (br. s., 1H) 1.37-1.70 (m, 3H). MS (LC/MS) R.T.=1.37; [M+H]⁺=312.2.Optical rotation=+35.99°.

Example 11N-(6-Ethoxybenzo[d]thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: N-(6-Ethoxybenzo[d]thiazol-2-yl)-1H-imidazole-1-carbothioamide

In a vial was placed 6-ethoxybenzo[d]thiazol-2-amine (1.5 g, 7.72 mmol)and di(′H-imidazol-1-yl)methanethione (1.789 g, 10.04 mmol) inacetonitrile (15 mL). The reaction was heated to 80° C. overnight. Thereaction mixture was filtered and the precipitate was collected toafford 2.4 grams (7.88 mmol, 102%) of rust-colored solids.

Step B:(3-((3-(6-Ethoxybenzo[d]thiazol-2-yl)thioureido)methyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate

In a vial was placedN-(6-ethoxybenzo[d]thiazol-2-yl)-¹H-imidazole-1-carbothioamide (2.4 g,7.88 mmol) and(3-(aminomethyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(1.341 g, 7.88 mmol) in N,N-dimethylformamide (8 mL). The reaction washeated to 80° C. After 2 hours the reaction was poured into water andchloroform and the organic was extracted and concentrated to a red oil.This material was used in the next reaction without any furtherpurification or characterization.

Step C:(2-(6-Ethoxybenzo[d]thiazol-2-ylamino)-4H-1′-ammoniospiro-[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate

In a flask was placed(3-((3-(6-ethoxybenzo[d]thiazol-2-yl)thioureido)-methyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(3.2 g, 7.9 mmol) and N,N′-diisopropylcarbodiimide (4.3 mL, 27.6 mmol)in N,N-dimethylformamide (10 mL). The reaction was heated to 70° C. for2 hours and then poured into water and chloroform. The organic wascollected and concentrated to a residue. The residue was triturated inether and the precipitate was collected via vacuum filtration to yield1.11 grams (2.98 mmol, 37.8%) of gray powder.

Step D:N-(6-Ethoxybenzo[d]thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

In a vial was placed(2-(6-ethoxybenzo[d]thiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate(500 mg, 1.34 mmol) and HCl (8.06 mL, 24.17 mmol) in acetone (10 mL).The reaction was monitored by HPLC. After 2 hours, the reaction wascomplete by LC/MS. The reaction was poured into water and chloroform,and the organic layer was set aside. The aqueous layer was neutralizedand extracted with chloroform (2×). The second chloroform fraction wasconcentrated to a white residue. The solid was triturated in ether andthe precipitate collected to yield 314.4 mg (0.877 mmol, 65.3%) of thedesired material. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.89 (1H, br. s.),7.50 (1H, d, J=8.81 Hz), 7.38 (1H, d, J=2.52 Hz), 6.91 (1H, dd, J=8.81,2.52 Hz), 4.03 (2H, q, J=7.05 Hz), 3.87 (1H, d, J=10.07 Hz), 3.62 (1H,d, J=10.07 Hz), 3.02 (2H, s), 2.78 (2H, t, J=7.81 Hz), 2.66 (2H, t,J=7.68 Hz), 2.05 (1H, br. s.), 1.91 (1H, br. s.), 1.42-1.67 (3H, m),1.33 (3H, t, J=7.05 Hz). MS (LC/MS) R.T.=1.60; [M+H]⁺=359.0.

The enantiomers were separated using a Chiralpak AS-H (30×250 mm, 5 μm)column with a mobile phase consisting of 30% methanol (0.1% DEA) in CO₂and UV monitored at 300 nm. The separated peaks were concentrated invacuo to yield white powders. The first peak off the column yielded 62.4mg, 0.17 mmol, 31.2%. (11a; S-isomer): ¹H NMR (500 MHz, DMSO-d₆) δ ppm8.87 (1H, br. s.), 7.49 (1H, d, J=8.55 Hz), 7.38 (1H, d, J=2.44 Hz),6.91 (1H, dd, J=8.85, 2.44 Hz), 4.03 (2H, q, J=7.02 Hz), 3.87 (1H, d,J=10.07 Hz), 3.61 (1H, d, J=10.07 Hz), 3.02 (2H, s), 2.72-2.85 (2H, m),2.66 (2H, t, J=7.63 Hz), 2.05 (1H, br. s.), 1.91 (1H, br. s.), 1.43-1.64(3H, m), 1.33 (3H, t, J=7.02 Hz). MS (LC/MS) R.T.=1.81; [M+H]⁺=359.1.The second peak yielded 58.9 mg, 0.164 mmol, 29.5%. (11b; R-isomer): ¹HNMR (500 MHz, DMSO-d₆) δ ppm 8.86 (1H, br. s.), 7.48 (1H, d, J=8.85 Hz),7.37 (1H, d, J=2.44 Hz), 6.91 (1H, d, J=2.75 Hz), 4.02 (2H, q, J=7.02Hz), 3.86 (1H, d, J=9.77 Hz), 3.61 (1H, d, J=9.77 Hz), 3.01 (2H, s),2.72-2.85 (2H, m), 2.62-2.69 (2H, m), 2.04 (1H, d, J=2.44 Hz), 1.90 (1H,d, J=4.27 Hz), 1.42-1.63 (3H, m), 1.29-1.35 (3H, m). MS (LC/MS)R.T.=1.52; [M+H]⁺=359.1.

Example 12N-(6-Methylbenzo[d]thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: N-(6-Methylbenzo[d]thiazol-2-yl)-¹H-imidazole-1-carbothioamide

To 6-methylbenzo[d]thiazol-2-amine (1. g, 6.2 mmol) in acetonitrile (30mL) was added 1,1′-thiocarbonyldiimidazole (1.44 g, 8.1 mmol). Thereaction was stirred at 50° C. for 18 hours. The reaction was cooled toroom temperature and the precipitate was filtered and washed withacetonitrile (2×50 mL). The yellow powder was dried in a vacuum oven(40° C.) for 1 hour to yieldN-(6-methylbenzo[d]thiazol-2-yl)-¹H-imidazole-1-carbothioamide (1.06 g,3.86 mmol, 62% yield) and then used in the next step without any furtherpurification or characterization.

Step B:(3-Hydroxy-3-((3-(6-methylbenzo[d]thiazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate

To N-(6-methylbenzo[d]thiazol-2-yl)-¹H-imidazole-1-carbothioamide (0.96g, 3.5 mmol) in N,N-dimethylformamide (20 mL) was added(3-(aminomethyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(0.595 g, 3.5 mmol). The reaction was stirred at 70° C. for 4 hours. Thereaction mixture was concentrated and purified via silica gelchromatography (40-100% ethyl acetate/hexanes). The product fractionswere concentrated in vacuo to yield(3-hydroxy-3-((3-(6-methylbenzo[d]thiazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(0.88 g, 2.338 mmol, 66.8% yield) as a white powder. MS (LC/MS)R.T.=3.71; [M+H]⁺=375.2.

Step C:(2-(6-Methylbenzo[d]thiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate

To(3-hydroxy-3-((3-(6-methylbenzo[d]thiazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(0.86 g, 2.285 mmol) in N,N-dimethylformamide (20 mL) was addedN,N′-diisopropylcarbodiimide (0.288 g, 2.285 mmol). The reaction wasstirred at 70° C. for 4 hours. The reaction was concentrated and ethylacetate was added. The precipitate was filtered and washed withadditional ethyl acetate. The powder was dried in a vacuum oven (70° C.)to yield(2-(6-methylbenzo[d]thiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate(0.65 g, 1.899 mmol, 83% yield) as a white powder. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 9.03 (1H, br. s.), 7.59 (1H, s), 7.51 (1H, d, J=8.24 Hz),7.15 (1H, d, J=8.24 Hz), 3.86 (1H, d, J=10.38 Hz), 3.74 (1H, d, J=10.38Hz), 3.29 (1H, dd, J=15.26, 1.83 Hz), 3.14 (1H, d, J=15.26 Hz),2.99-3.09 (1H, m), 2.80-2.95 (3H, m), 2.36 (3H, s), 2.25 (1H, br. s.),2.03 (1H, t, J=10.22 Hz), 1.70-1.85 (3H, m). MS (LC/MS) R.T.=2.78;[M+H]⁺=343.2.

Step D:N-(6-Methylbenzo[d]thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To(2-(6-methylbenzo[d]thiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate(0.24 g, 0.70 mmol) in acetone (9 mL) was added 3 M HCl (1.753 mL, 5.26mmol). The reaction mixture was stirred at room temperature for 4 hours.Ethyl acetate was added and the aqueous layer was collected andneutralized with 1N sodium hydroxide. The product was extracted withethyl acetate (2×40 mL). The organics were combined, dried withmagnesium sulfate, filtered and concentrated in vacuo to affordN-(6-methylbenzo[d]thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.19 g, 0.58 mmol, 83% yield) as a white powder. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.96 (1H, br. s.), 7.57 (1H, s), 7.49 (1H, d, J=8.24 Hz),7.13 (1H, d, J=8.24 Hz), 3.88 (1H, d, J=10.07 Hz), 3.63 (1H, d, J=9.77Hz), 2.98-3.04 (2H, m), 2.72-2.85 (2H, m), 2.66 (2H, t, J=7.63 Hz), 2.36(3H, s), 2.05 (1H, d, J=2.14 Hz), 1.91 (1H, br. s.), 1.53-1.64 (2H, m),1.42-1.53 (1H, m). MS (LC/MS) R.T.=1.79; [M+H]⁺=329.2.

The enantiomers were separated using a Chiralcel OJ-H (4.6×25 cm, 5 μm)column with 30% methanol (0.1% DEA) in CO₂ and UV monitored at 300 nm.The separated peaks were concentrated in vacuo to yield white powders.The first peak off the column yielded 0.11 g, 0.34 mmol, 55%. (12a;R-isomer): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.95 (s, 1H), 7.57 (s, 2H),7.48 (d, J=8.24 Hz, 2H), 7.13 (d, J=8.24 Hz, 2H), 3.89 (d, J=10.38 Hz,2H), 3.63 (d, J=10.38 Hz, 2H), 2.99-3.06 (m, 4H), 2.75-2.84 (m, 4H),2.67 (t, J=7.63 Hz, 4H), 2.37 (s, 7H), 2.06 (s, 2H), 1.92 (s, 2H),1.55-1.64 (m, 4H), 1.49 (dd, J=9.77, 2.44 Hz, 2H). MS (LC/MS) R.T.=1.80;[M+H]⁺=329.2. Optical rotation=−4.52. The second peak yielded 0.11 g,0.34 mmol, 55%. (12b; S-isomer): ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.96(s, 1H), 7.58 (s, 1H), 7.49 (d, J=8.24 Hz, 1H), 7.14 (d, J=8.24 Hz, 1H),3.89 (d, J=10.07 Hz, 1H), 3.63 (d, J=10.07 Hz, 1H), 3.03 (d, J=2.44 Hz,2H), 2.75-2.84 (m, 2H), 2.67 (t, J=7.78 Hz, 2H), 2.37 (s, 3H), 2.06 (s,1H), 1.92 (s, 1H), 1.55-1.64 (m, 2H), 1.49 (dd, J=9.77, 2.75 Hz, 1H). MS(LC/MS) R.T.=1.80; [M+H]⁺=329.2. Optical rotation=+10.08.

Example 132-(4H-1′-Azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]-2-ylamino)benzo[d]thiazol-6-ol

Step A:N-(6-(tert-Butyldimethylsilyloxy)benzo[d]thiazol-2-yl)-1H-imidazole-1-carbothioamide

To 6-(tert-butyldimethylsilyloxy)benzo[d]thiazol-2-amine (prepared asdescribed in WO 2007/086800 p.102) (3.1 g, 11.05 mmol) in acetonitrile(30 mL) was added thiocarbonyl diimidazole (2.56 g, 14.37 mmol). Thereaction was heated to 70° C. overnight. The reaction was cooled to roomtemperature and the precipitate was filtered and washed withacetonitrile to afford a yellow solid. The product,N-(6-(tert-butyldimethylsilyloxy)benzo[d]thiazol-2-yl)-1H-imidazole-1-carbothioamide(3.85 g, 9.86 mmol, 89% yield), was taken directly to the next stepwithout any further purification. MS (LC/MS) R.T.=2.56; [M+H]⁺=388.9.

Step B:(3-((3-(6-(tert-Butyldimethylsilyloxy)benzo[d]thiazol-2-yl)thioureido)methyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate

ToN-(6-(tert-butyldimethylsilyloxy)benzo[d]thiazol-2-yl)-1H-imidazole-1-carbothioamide(3.85 g, 9.86 mmol) in N,N-dimethylformamide (40 mL) was added(3-(aminomethyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(1.68 g, 9.86 mmol). The reaction was heated at 80° C. for 2 hours. Thereaction was cooled and then poured into a mixture of chloroform andwater. The organic layer was collected and concentrated in vacuo toafford(3-((3-(6-(tert-butyldimethylsilyloxy)benzo[d]thiazol-2-yl)thioureido)methyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(6.2 g) as a yellow oil.

Step C:(2-(6-(tert-Butyldimethylsilyloxy)benzo[d]thiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate

To(3-((3-(6-(tert-butyldimethylsilyloxy)benzo[d]thiazol-2-yl)thioureido)methyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(4.9 g, 9.9 mmol) in N,N-dimethylformamide (10 mL) was added1,3-diisopropylcarbodiimide (5.4 mL, 34.5 mmol). The reaction was heatedto 80° C. and monitored by LC/MS. The reaction was cooled and thenpoured into a mixture of chloroform and water. The organic layer wascollected and concentrated in vacuo. The remaining residue wastriturated in ether. The precipitate was collected to afford(2-(6-(tert-butyldimethylsilyloxy)benzo[d]thiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate(3.28 g, 7.15 mmol, 72.6% yield). MS (LC/MS) R.T.=3.60;[M+H−BH₃]⁺=445.2.

Step D:2-(4H-1′-Azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]-2-ylamino)benzo[d]thiazol-6-ol

To(2-(6-(tert-butyldimethylsilyloxy)benzo[d]thiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate(3.2 g, 6.98 mmol) in acetone (10 mL) was added HCl (8.14 mL, 24.43mmol). The reaction was stirred at room temperature for 3 hours. Themixture was poured into water and neutralized with saturated sodiumbicarbonate. The aqueous layer was then extracted with chloroform. Theorganic layer was collected and concentrated in vacuo. The remainingresidue was triturated in ether to afford racemic2-(4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]-2-ylamino)benzo[d]thiazol-6-ol(958 mg, 2.90 mmol, 41.5% yield) as a white powder. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 9.36 (1H, br. s.), 8.85 (1H, br. s.), 7.41 (1H, d, J=8.85Hz), 7.12 (1H, d, J=2.44 Hz), 6.78 (1H, dd, J=8.85, 2.44 Hz), 3.86 (1H,d, J=10.07 Hz), 3.61 (1H, d, J=10.07 Hz), 2.96-3.06 (2H, m), 2.71-2.85(2H, m), 2.66 (2H, t, J=7.78 Hz), 2.04 (1H, br. s.), 1.90 (1H, br. s.),1.43-1.64 (3H, m). MS (LC/MS) R.T.=1.03; [M+H]⁺=331.29.

The enantiomers were separated using a Chiralpak AD-H (30×250 mm, 5 μm)column with a mobile phase consisting of 30% methanol (0.1% DEA) in CO₂.The wavelength was set at 300 nM. The separated peaks were concentratedin vacuo to yield white powders. The first peak off the column was(S)-2-(4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]-2-ylamino)benzo[d]thiazol-6-ol(395.2 mg, 1.19 mmol, 41.4% yield). (13a, S-isomer): ¹H NMR (500 MHz,DMSO-d₆) δ ppm 9.36 (1H, br. s.), 8.84 (1H, br. s.), 7.41 (1H, d, J=8.55Hz), 7.12 (1H, d, J=2.44 Hz), 6.78 (1H, dd, J=8.55, 2.44 Hz), 3.86 (1H,d, J=9.77 Hz), 3.61 (1H, d, J=10.07 Hz), 2.96-3.05 (2H, m), 2.72-2.84(2H, m), 2.65 (2H, t, J=7.63 Hz), 2.04 (1H, br. s.), 1.90 (1H, br. s.),1.52-1.64 (2H, m), 1.43-1.52 (1H, m). MS (LC/MS) R.T.=1.30;[M+H]⁺=331.4. The second peak was(R)-2-(4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]-2-ylamino)benzo[d]thiazol-6-ol(375 mg, 1.14 mmol, 39.3% yield). (13b, R-isomer): ¹H NMR (500 MHz,DMSO-d₆) δ ppm 7.40 (1H, d, J=8.55 Hz), 7.11 (1H, d, J=2.44 Hz), 6.77(1H, dd, J=8.55, 2.44 Hz), 3.86 (1H, d, J=10.07 Hz), 3.60 (1H, d,J=10.07 Hz), 3.01 (2H, s), 2.73-2.84 (2H, m), 2.65 (2H, t, J=7.78 Hz),2.04 (1H, br. s.), 1.90 (1H, br. s.), 1.54-1.62 (2H, m), 1.43-1.52 (1H,m). MS (LC/MS) R.T.=1.43; [M+H]⁺=331.4.

Example 14N-(4,5,6,7-Tetrahydrobenzo[d]thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A:N-(4,5,6,7-Tetrahydrobenzo[d]thiazol-2-yl)-1H-imidazole-1-carbothioamide

To 4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (0.5 g, 3.24 mmol) inacetonitrile (20 mL) was added di(1H-imidazol-1-yl)methanethione (0.58g, 3.24 mmol). The reaction was stirred at 50° C. for 4 hours. Thereaction was cooled and concentrated to yield crude product. The crudematerial was purified via flash chromatography (50-100% ethylacetate-hexane) to yieldN-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-1H-imidazole-1-carbothioamide(0.60 g, 2.27 mmol, 70.0% yield) as a white powder.

Step B:(3-Hydroxy-3-((3-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate

ToN-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-1H-imidazole-1-carbothioamide(0.54 g, 2 mmol) in N,N-dimethylformamide (20 mL) was added(3-(aminomethyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(0.35 g, 2 mmol). The reaction was stirred at 50° C. for 3 hours. Thereaction was cooled and concentrated to yield crude product. The crudematerial was purified via flash chromatography (50-100% ethylacetate-hexane) yielding the first spot/fractions (TLC) as the product.The fractions were combined and concentrated to yield(3-hydroxy-3-((3-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(0.51 g, 1.39 mmol, 68.2% yield) as a white powder. ¹H NMR (500 MHz,DMSO-D6) δ ppm 11.46 (s, 1H), 5.26 (s, 1H), 3.89 (dd, J=13.58, 5.34 Hz,1H), 3.68 (dd, J=13.73, 4.88 Hz, 1H), 2.55-2.94 (m, 8H), 2.06 (dd,J=9.31, 3.20 Hz, 1H), 1.66-1.90 (m, 6H), 1.21-1.59 (m, 4H);[M+H]⁺=365.1.

Step C:(2-(4,5,6,7-Tetrahydrobenzo[d]thiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate

To(3-hydroxy-3-((3-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(0.5 g, 1.37 mmol) in N,N-dimethylformamide (20 mL) was addedN,N-diisopropylcarbodiimide (0.74 mL, 4.78 mmol). The reaction wasstirred at 70° C. for 4 hours. The reaction was concentrated to yield acrude residue. The crude material was purified via flash chromatography(50-100% ethyl acetate-hexanes) yielding the second spot/fractions (TLC)as the product. The fractions were combined and concentrated to yield(2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate(0.38 g, 1.14 mmol, 84% yield) as a white powder. ¹H NMR (500 MHz,DMSO-D6) δ ppm 8.26-8.86 (m, 1H), 3.78 (d, J=9.46 Hz, 1H), 3.66 (d,J=9.77 Hz, 1H), 3.19-3.30 (m, J=14.95, 2.14 Hz, 1H), 2.96-3.12 (m, 2H),2.78-2.94 (m, 3H), 2.54-2.65 (m, 4H), 2.19 (s, 1H), 2.00 (s, 1H),1.66-1.85 (m, 7H), 1.43 (m, 3H). MS (LC/MS) R.T.=2.50; [M+H−BH₃]⁺=319.1.

Step D:N-(4,5,6,7-Tetrahydrobenzo[d]thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To(2-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate(0.36 g, 1.08 mmol) in acetone (9 mL) was added 3M HCl (0.36 mL, 1.08mmol). The reaction was stirred at room temperature for 4 hours. Thereaction was complete by TLC (lower spot). Ethyl acetate was added andthe aqueous layer was then separated. The aqueous layer was neutralizedwith 1N sodium hydroxide. The product was extracted with ethyl acetate(2×40 mL). The organics were combined, dried with magnesium sulfate,filtered, and concentrated in vacuo to afford racemicN-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.28 g, 0.84 mmol, 78% yield) as a white powder. ¹H NMR (500 MHz,DMSO-D6) δ ppm 8.30-8.75 (br.s, 1H), 3.79 (d, J=9.44 Hz, 1H), 3.55 (d,J=9.76 Hz, 1H), 2.90-3.03 (m, 2H), 2.54-2.84 (m, 8H), 2.00 (s, 1H),1.81-1.93 (m, 1H), 1.75 (d, J=2.44 Hz, 4H), 1.36-1.67 (m, 3H). MS(LC/MS) R.T.=1.39; [M+H]⁺=319.1.

The enantiomers were separated using a Chiralpak AD-H (30×250 mm, 5 μm)column with a mobile phase consisting of 23% methanol (0.1% DEA) in CO₂.The wavelength was set at 300 nM. The separated peaks were concentratedin vacuo to yield white powders. The first peak off the column was(S)—N-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.1 g, 0.29 mmol, 36.8% yield). (14a, S-isomer): ¹H NMR (500 MHz,DMSO-D6) δ ppm 8.29-8.89 (br.s, 1H), 3.80 (d, J=9.46 Hz, 1H), 3.54 (d,J=9.77 Hz, 1H), 2.94-3.04 (m, 2H), 2.55-2.85 (m, 8H), 2.00 (s, 1H),1.85-1.94 (m, 1H), 1.70-1.81 (m, J=2.43 Hz, 4H), 1.39-1.65 (m, 3H). MS(LC/MS) R.T.=1.54; [M+H]⁺=319.1. The second peak was(R)—N-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.11 g, 0.30 mmol, 38.2% yield). (14b, R-isomer): ¹H NMR (500 MHz,DMSO-D6) δ ppm 8.24-8.96 (br.s, 1H), 3.79 (d, J=9.46 Hz, 1H), 3.52 (d,J=9.76 Hz, 1H), 2.95-3.08 (m, 2H), 2.55-2.80 (m, 8H), 2.00 (s, 1H),1.85-1.90 (m, 1H), 1.70-1.79 (m, J=2.42 Hz, 4H), 1.39-1.63 (m, 3H);[M+H]⁺=319.1.

Example 15N-(4-Isopropylthiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: N-(4-Isopropylthiazol-2-yl)-1H-imidazole-1-carbothioamide

To 4-isopropylthiazol-2-amine (1.04 g, 7.31 mmol) in acetonitrile (30mL) was added 1,1-thiocarbonyldiimidazole (1.7 g, 9.5 mmol). Thereaction was stirred at 50° C. for 18 hours. The reaction was cooled toroom temperature and the precipitate was filtered and washed withacetonitrile (2×50 mL). The yellow powder was dried in a vacuum oven(40° C.) for 2 hours. The product,N-(4-isopropylthiazol-2-yl)-1H-imidazole-1-carbothioamide (1.02 g, 4.04mmol, 55.3% yield), was taken directly to the next step without anyfurther purification.

Step B:(3-Hydroxy-3-((3-(4-isopropylthiazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate

To N-(4-isopropylthiazol-2-yl)-1H-imidazole-1-carbothioamide (0.57 g,2.26 mmol) in N,N-dimethylformamide (20 mL) was added(3-(aminomethyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(0.38 g, 2.26 mmol). The reaction was stirred at 70° C. for 24 hours.The reaction was cooled and concentrated to yield crude product. Thecrude material was purified via flash chromatography (50-100% ethylacetate-hexane) to yield(3-hydroxy-3-((3-(4-isopropylthiazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(0.56 g, 1.58 mmol, 70.0% yield) as a white powder. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 11.62 (s, 1H), 6.70 (s, 1H), 5.31 (s, 1H), 3.58-3.96 (m,2H), 2.63-3.11 (m, 7H), 2.00-2.22 (m, 1H), 1.65-1.97 (m, 3H), 1.16-1.61(m, 10H). MS (LC/MS) R.T.=3.43; [M+H]⁺=353.2.

Step C:(2-(5-Isopropylthiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate

To(3-hydroxy-3-((3-(5-isopropylthiazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(0.54 g, 1.52 mmol) in N,N-dimethylformamide (20 mL) was addedN,N′-diisopropylcarbodiimide (0.83 mL, 5.33 mmol). The reaction wasstirred at 50° C. for 24 hours. The reaction was concentrated to yield acrude residue. The crude material was purified via flash chromatography(50-100% ethyl acetate-hexanes) yielding the second spot/fractions (TLC)as the product. The fractions were combined and concentrated to yield(2-(5-isopropylthiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate(0.39 g, 1.22 mmol, 80% yield) as a white powder. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 6.55 (s, 1H), 3.75 (m, 2H), 3.20-3.31 (m, 1H), 2.96-3.15(m, 2H), 2.77-2.97 (m, 4H), 2.22 (s, 1H), 2.01 (s, 1H), 1.68-1.90 (m,3H), 1.43 (s, 3H), 1.21 (d, J=7.02 Hz, 6H). MS (LC/MS) R.T.=2.36;[M+H−BH₃]⁺=307.2.

Step D:N-(4-Isopropylthiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To(2-(4-isopropylthiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate(0.42 g, 1.31 mmol) in acetone (9 mL) was added 3M HCl (0.44 mL, 1.31mmol). The reaction was stirred at room temperature for 4 hours. Thereaction was complete by TLC (lower spot). Ethyl acetate was added andthe aqueous layer was then separated. The aqueous layer was neutralizedwith 1N sodium hydroxide. The product was extracted with ethyl acetate(2×40 mL). The organics were combined, dried with magnesium sulfate,filtered, and concentrated in vacuo to afford racemicN-(4-isopropylthiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.34 g, 1.05 mmol, 80% yield) as a white powder. ¹H NMR (500 MHz,DMSO-D6) δ ppm 8.20-8.91 (m, 1H), 6.52 (s, 1H), 3.83 (d, J=9.46 Hz, 1H),3.57 (d, J=9.46 Hz, 1H), 2.99 (s, 2H), 2.58-2.92 (m, 5H), 2.02 (s, 1H),1.82-1.96 (m, 1H), 1.38-1.66 (m, 3H), 1.20 (d, J=7.02 Hz, 6H). MS(LC/MS) R.T.=1.27; [M+H]⁺=307.1.

The enantiomers were separated using a Chiralcel OJ-H (30×250 mm, 5 μm)column with a mobile phase consisting of 23% methanol (0.1% DEA) in CO₂.The wavelength was set at 300 nM. The separated peaks were concentratedin vacuo to yield white powders. The first peak off the column was(S)—N-(4-isopropylthiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.01 g, 0.03 mmol, 2.95% yield). (15a, S-isomer): ¹H NMR (500 MHz,DMSO-D6) δ ppm 8.35-8.95 (m, 1H), 6.52 (s, 1H), 3.82 (d, J=9.41 Hz, 1H),3.57 (d, J=9.46 Hz, 1H), 2.99 (s, 2 H), 2.60-2.88 (m, 5H), 2.02 (s, 2H),1.82-1.96 (m, 1H), 1.38-1.65 (m, 3H), 1.20 (d, J=6.71 Hz, 6H). MS(LC/MS) R.T.=1.38; [M+H]⁺=307.1. The second peak was(R)—N-(4-isopropylthiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.02 g, 0.05 mmol, 4.83% yield). (15b, R-isomer):

¹H NMR (500 MHz, DMSO-D6) δ ppm 8.35-8.91 (m, 1H), 6.52 (s, 1H), 3.82(d, J=9.44 Hz, 1H), 3.57 (d, J=9.46 Hz, 1H), 2.99 (s, 2H), 2.60-2.90 (m,5H), 2.02 (s, 2H), 1.82-1.96 (m, 1H), 1.38-1.62 (m, 3H), 1.20 (d, J=6.78Hz, 6H). MS (LC/MS) R.T.=1.49; [M+H]⁺=307.3.

Example 16N-(Thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: N-(Thiazol-2-yl)-1H-imidazole-1-carbothioamide

To thiazol-2-amine (2.12 g, 21.17 mmol) in acetonitrile (30 mL) andtetrahydrofuran (5 mL) was added di(1H-imidazol-1-yl)methanethione (4.90g, 27.5 mmol). The reaction was stirred at 60° C. for 5 hours. Thereaction was cooled to room temperature and the precipitate was filteredand washed with cold acetonitrile (2×15 mL) to afford an orange-brownpowder. The product, N-(thiazol-2-yl)-1H-imidazole-1-carbothioamide(3.70 g, 17.60 mmol, 83% yield), was taken directly to the next stepwithout any further characterization.

Step B:(3-Hydroxy-3-((3-thiazol-2-ylthioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate

To N-(thiazol-2-yl)-1H-imidazole-1-carbothioamide (1.7 g, 8 mmol) inN,N-dimethylformamide (30 mL) was added(3-(aminomethyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(1.37 g, 8 mmol). The reaction was stirred at 50° C. for 4 hours. Thereaction was cooled and concentrated to yield crude product. The crudematerial was purified via flash chromatography (50-100% ethylacetate-hexane) yielding the first spot/fractions (TLC) as the product.The fractions were combined and concentrated to yield(3-hydroxy-3-((3-thiazol-2-ylthioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(1.5 g, 4.80 mmol, 59.8% yield) as a white powder. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 11.64 (s, 1H), 7.42 (d, J=3.36 Hz, 1H), 7.14 (m, 1H),5.32 (s, 1H), 3.78 (dd, 2H), 2.59-3.02 (m, 6H), 1.99-2.18 (m, 1H),1.79-1.92 (m, 2H), 1.64-1.80 (m, 1H), 1.19-1.65 (m, 4H). MS (LC/MS)R.T.=2.73; [M+H]⁺=311.1.

Step C:(2-(Thiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate

To(3-hydroxy-3-((3-thiazol-2-ylthioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(1.2 g, 3.84 mmol) in N,N-dimethylformamide (20 mL) was addedN,N′-diisopropylcarbodiimide (2.09 mL, 13.45 mmol). The reaction wasstirred at 50° C. for 24 hours. The reaction was concentrated to yield acrude residue. The crude material was purified via flash chromatography(50-100% ethyl acetate-hexane) yielding the first spot/fractions (TLC)as the product. The fractions were combined and concentrated to yield(2-(thiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate(0.84 g, 3.02 mmol, 79% yield) as a white powder. ¹H NMR (500 MHz,DMSO-D6) δ ppm 8.37-9.14 (m, 1H), 7.32 (d, J=3.66 Hz, 1H), 7.04 (d,J=3.66 Hz, 2H), 3.79 (d, J=10.07 Hz, 1H), 3.67 (d, J=10.07 Hz, 1H),3.20-3.29 (m, J=14.95, 2.14 Hz, 1H), 2.97-3.15 (m, 2H), 2.78-2.94 (m,3H), 2.22 (s, 1H), 1.95-2.08 (m, 1H), 1.66-1.85 (m, 3H), 1.43 (s, 3H).MS (LC/MS) R.T.=1.57; [M+H−BH₃]⁺=265.1.

Step D:N-(Thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To(2-(thiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate(0.57 g, 2.05 mmol) in acetone (9 mL) was added 3M HCl (0.68 mL, 2.05mmol). The reaction was stirred at room temperature for 4 hours. Thereaction was complete by TLC (lower spot). Ethyl acetate was added andthe aqueous layer was then separated. The aqueous layer was neutralizedwith 1N sodium hydroxide. The product was extracted with ethyl acetate(2×40 mL). The organics were combined, dried with magnesium sulfate,filtered, and concentrated in vacuo to afford racemicN-(thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.4 g, 1.44 mmol, 70.2% yield) as a white powder. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.64 (s, 1H), 7.24 (d, J=3.74 Hz, 2H), 7.01 (d, J=3.75Hz, 2H), 3.78 (d, J=9.80 Hz, 2H), 3.53 (d, J=9.80 Hz, 2H), 2.97-3.05 (m,4H), 2.74-2.86 (m, 4H), 2.65 (t, J=7.84 Hz, 4H), 2.01 (s, 2H), 1.88 (s,2H), 1.53-1.64 (m, 4H), 1.45-1.56 (m, 2H). MS (LC/MS) R.T.=0.28;[M+H]⁺=265.1.

The enantiomers were separated using a Chiralcel OJ-H (30×250 mm, 5 μm)column with a mobile phase consisting of 23% methanol (0.1% DEA) in CO₂.The wavelength was set at 300 nM. The separated peaks were concentratedin vacuo to yield white powders. The first peak off the column was(S)—N-(thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.12 g, 0.43 mmol, 18.80% yield). (16a, S-isomer): ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.64 (s, 1H), 7.26 (d, J=3.75 Hz, 2H), 7.00 (d, J=3.77Hz, 2H), 3.78 (d, J=9.81 Hz, 2H), 3.54 (d, J=9.82 Hz, 2H), 2.95-3.10 (m,4H), 2.75-2.82 (m, 4H), 2.65 (t, J=7.80 Hz, 4H), 2.01 (s, 2H), 1.88 (s,2H), 1.53-1.60 (m, 4H), 1.42-1.51 (m, 2H). MS (LC/MS) R.T.=0.32;[M+H]⁺=265.1. The second peak was(R)—N-(thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.15 g, 0.52 mmol, 22.96% yield). (16b, R-isomer): ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.64 (s, 1H), 7.25 (d, J=3.74 Hz, 2H), 7.00 (d, J=3.76Hz, 2H), 3.78 (d, J=9.80 Hz, 2H), 3.53 (d, J=9.80 Hz, 2H), 2.95-3.08 (m,4H), 2.75-2.84 (m, 4H), 2.65 (t, J=7.80 Hz, 4H), 2.01 (s, 2H), 1.88 (s,2H), 1.54-1.62 (m, 4H), 1.43-1.53 (m, 2H). MS (LC/MS) R.T.=0.28;[M+H]⁺=265.3.

Example 17N-(4-(4-Methoxyphenyl)-5-methylthiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A:N-(4-(4-Methoxyphenyl)-5-methylthiazol-2-yl)-1H-imidazole-1-carbothioamide

To 4-(4-methoxyphenyl)-5-methylthiazol-2-amine (0.98 g, 4.45 mmol) inacetonitrile (25 mL) was added di(1H-imidazol-1-yl)methanethione (1.03g, 5.78 mmol). The reaction was stirred at 50° C. for 3 hours. Thereaction was cooled to room temperature and the precipate was filtered.The powder was washed with acetonitrile (2×10 mL) and dried to yieldracemicN-(4-(4-methoxyphenyl)-5-methylthiazol-2-yl)-1H-imidazole-1-carbothioamide(1.28 g, 3.87 mmol, 87% yield) as a yellow powder. The product was takendirectly to the next step.

Step B:(2-(4-(4-Methoxyphenyl)-5-methylthiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate

ToN-(4-(4-methoxyphenyl)-5-methylthiazol-2-yl)-1H-imidazole-1-carboxamide(0.44 g, 1.39 mmol) in N,N-dimethylformamide (25 mL) was added(3-(aminomethyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(0.24 g, 1.39 mmol). The reaction was stirred at 70° C. for 2 hours.N,N′-Diisopropylcarbodiimide (0.65 mL, 4.16 mmol) was added and thereaction heated to 75° C. for 2 hours. The reaction was cooled andconcentrated to afford the crude product. The crude material waspurified via column chromatography (60-100% ethyl acetate/hexanes) toyield(2-(4-(4-methoxyphenyl)-5-methylthiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate(0.41 g, 1.029 mmol, 74.2% yield) as a yellow powder. ¹H NMR (500 MHz,DMSO-D6) δ ppm 7.59 (d, J=7.63 Hz, 2H), 6.98 (d, J=8.55 Hz, 2H), 3.80(s, 4H), 3.67 (s, 1H), 3.24-3.31 (m, 1H), 3.13 (s, 1H), 3.03 (s, 1H),2.83-2.92 (m, 3H), 2.39 (s, 3H), 2.23 (s, 1H), 2.07 (s, 1H), 1.73-1.82(m, 2H), 1.44 (s, 1H). MS (LC/MS) R.T.=2.88; [M+H]⁺=399.34.

Step C:N-(4-(4-Methoxyphenyl)-5-methylthiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To(3-hydroxy-3-((3-(4-(4-methoxyphenyl)-5-methylthiazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(0.08 g, 0.19 mmol) in acetone (9 mL) was added 2M HCl (0.09 mL, 0.19mmol). The reaction was stirred at room temperature for 1 hour. Thereaction was complete by TLC (lower spot). Ethyl acetate was added andthe aqueous layer was collected and neutralized with 1N sodiumhydroxide. The product was extracted with ethyl acetate (2×40 mL). Theorganics were combined, dried with magnesium sulfate, filtered, andconcentrated in vacuo to afford racemicN-(4-(4-methoxyphenyl)-5-methylthiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.05 g, 0.12 mmol, 66.8% yield) as a white powder. ¹H NMR (500 MHz,DMSO-D6) δ ppm 7.58 (d, J=8.24 Hz, 2H), 6.98 (d, J=8.55 Hz, 2H), 3.83(d, J=9.16 Hz, 1H), 3.80 (s, 3H), 3.56 (d, J=9.46 Hz, 1H), 3.00 (s, 2H),2.74-2.83 (m, 2H), 2.66 (t, J=7.63 Hz, 2H), 2.38 (s, 3H), 2.03 (s, 1H),1.91 (s, 1H), 1.54-1.62 (m, 2H), 1.48 (d, J=7.02 Hz, 1H). MS (LC/MS)R.T.=2.04; [M+H]⁺=385.28.

Example 18(E)-N-(1′-Azaspiro[oxazolidine-5,3′-bicyclo[2.2.2]octane]-2-ylidene)pyridin-3-amine

Step A:(3-Hydroxy-3-((3-pyridin-3-ylthioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate

To a stirring suspension of(3-(aminomethyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(247 mg, 1.45 mmol) in tetrahydrofuran (3 mL) was added a solution of3-isothiocyanatopyridine (298 mg, 2.19 mmol) in tetrahydrofuran (1.5 mL)and the reaction mixture was stirred at room temperature overnight. Thereaction mixture was evaporated in vacuo and the residue (white waxysolid) purified via column chromatography (3% methanol/ethyl acetate) toyield(3-hydroxy-3-((3-pyridin-3-ylthioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(294.6 mg, 0.96 mmol, 66.2% yield) as a white foam. ¹H NMR (500 MHz,MeOD-d₄) δ ppm 8.56-8.70 (m, 1H), 8.24-8.36 (m, 1H), 8.08-8.16 (m, 1H),7.32-7.48 (m, 1H), 4.02-4.18 (m, 1H), 3.67-3.77 (m, 1H), 3.53-3.62 (m,1H), 2.88-3.11 (m, 3H), 2.70-2.88 (m, 1H), 2.15-2.29 (m, 1H), 1.92-2.12(m, 2H), 1.73-1.89 (m, 1H), 1.54-1.69 (m, 2H).

MS (LC/MS) R.T.=1.00; [MH⁺—BH₃]=293.10.

Step B:(E)-(2-(Pyridin-3-ylimino)-1′-ammoniospiro[oxazolidine-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate

To a solution of(3-hydroxy-3-(3-pyridin-3-ylthioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(294.6 mg, 0.96 mmol) in N,N-dimethylformamide (5 mL) was added asolution of N,N′-methanediylidenedipropan-2-amine (121 mg, 0.96 mmol) inN,N-dimethylformamide (1 mL) and the reaction mixture was allowed tostand at room temperature for 7 days. An additional 133 mgN,N′-methanediylidenedipropan-2-amine in 0.5 mL N,N-dimethylformamidewas added and the reaction was left to continue for another 7 days. Thereaction was purified via column chromatography (5-10% methanol/ethylacetate) to afford(E)-(2-(pyridin-3-ylimino)-1′-ammoniospiro[oxazolidine-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate(134.3 mg, 0.49 mmol, 51.3% yield). ¹H NMR (500 MHz, MeOD) δ ppm8.34-8.60 (m, 1H), 8.16 (d, J=4.27 Hz, 1H), 7.59-7.96 (m, 1H), 7.35 (dd,J=8.24, 4.88 Hz, 1H), 3.89 (br. s., 1H), 3.65 (d, J=9.46 Hz, 1H),3.16-3.23 (m, 1H), 3.04-3.16 (m, 1H), 2.85-3.04 (m, 2H), 2.23 (br. s.,1H), 1.74-1.97 (m, 4H), 1.36-1.70 (m, 2H). MS (LC/MS) R.T.=0.65;[M+H−BH₃]⁺=259.21.

Step C:(E)-N-(1′-Azaspiro[oxazolidine-5,3′-bicyclo[2.2.2]octane]-2-ylidene)pyridin-3-amine

To a suspension of(E)-(2-(pyridin-3-ylimino)-1′-ammoniospiro[oxazolidine-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate(127 mg, 0.47 mmol) in acetone (5 mL) was added 3M hydrochloric acid (2mL, 6.00 mmol) and the mixture was allowed to stand at room temperaturefor 2 hrs. It was then added it to a reparatory funnel containing waterand chloroform. The layers were separated, then the aqueous layer wasmade basic with sodium carbonate solution and the mixture wasre-extracted with chloroform. Finally, the aqueous phase was washed withethyl acetate. The organics were combined, dried with magnesium sulfate,filtered, and concentrated in vacuo. The residue was purified by columnchromatography (1% ammonium hydroxide/9% methanol/90% dichloromethane)to afford racemic(E)-N-(1′-azaspiro[oxazolidine-5,3′-bicyclo[2.2.2]octane]-2-ylidene)pyridin-3-amine(19 mg, 0.074 mmol, 15.8% yield) as a white solid. ¹H NMR (500 MHz,MeOD-d₄) δ ppm 8.39 (br. s., 1H), 8.14 (d, J=4.27 Hz, 1H), 7.72 (br. s.,1H), 7.34 (dd, J=8.24, 4.88 Hz, 1H), 3.89 (d, J=9.77 Hz, 1H), 3.57 (d,J=10.38 Hz, 1H), 3.14-3.27 (m, 1H), 3.00-3.13 (m, 1H), 2.70-3.00 (m,4H), 1.97-2.22 (m, 2H), 1.54-1.84 (m, 3H). MS (LC/MS) R.T.=0.26;[M+H]⁺=259.16.

Example 19N-(Pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 2-Bromo-6-isothiocyanatopyridine

A mixture of 6-bromopyridin-2-amine (253 mg, 1.46 mmol), chloroform (2mL), sodium bicarbonate (850 mg, 10.12 mmol) and water (3 mL) wasassembled, and to this was added a solution of thiophosgene (190 mg,1.65 mmol) in chloroform (1 mL). The reaction mixture was stirred atroom temperature for 4 hours. The reaction mixture was transferred to aseparatory funnel and partitioned between ethyl acetate and water. Theorganic layer was washed with brine, dried over magnesium sulfate,filtered and the solvent evaporated to give a yellow solid. The solidwas purified by column chromatography (5% ethyl acetate/hexanes) toafford 2-bromo-6-isothiocyanatopyridine (281 mg, 1.31 mmol, 89% yield)as a white solid. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.50-7.62 (m, 1H),7.34-7.43 (m, 1H), 6.91-7.11 (m, 1H). MS (LC/MS) R.T.=1.92;[M+H]⁺=216.86.

Step B:N-(6-Bromopyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To a solution of 2-bromo-6-isothiocyanatopyridine (281 mg, 1.31 mmol) inN,N-dimethylformamide (8 mL) and Hunig's base (0.6 mL, 3.44 mmol) wasadded (+/−) 3-(aminomethyl)quinuclidin-3-ol dihydrochloride (300 mg,1.31 mmol) and the resulting mixture was heated to 75° C. for 2.5 hrs.MS (LC/MS) R.T.=1.04; [M+H]⁺=373.01. To this reaction mixture was addeddi-isopropyl-carbodiimide (523 mg, 4.14 mmol) and the heating at 75° C.was continued for 2.25 hours. The mixture was allowed to cool to roomtemperature over the weekend. The reaction mixture was concentrated invacuo. The material was purified by column chromatography thenpreparative HPLC to affordN-(6-bromopyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(291.5 mg, 0.86 mmol, 66.25 yield) as a yellow solid (containing2-amino-6-bromopyridine impurity). MS (LC/MS) R.T.=0.65; [M+H]⁺=337.0.

Step C:N-(Pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

ToN-(6-bromopyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(291 mg, 0.86 mmol) in methanol (20 mL) was hydrogenated over 10%palladium on carbon (23 mg) in the Parr apparatus for 2 hours. Thecatalyst was removed by filtration and the filtrated concentrated invacuo. The residue was purified by column chromatography (0.7% ammoniumhydroxide/6.3% methanol/93% chloroform) to give racemicN-(pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(41.3 mg, 0.16 mmol, 18.65 yield). ¹H NMR (500 MHz, MeOD) δ ppm8.13-8.33 (m, 1H), 7.57-7.72 (m, 1H), 6.83-7.04 (m, 2H), 3.97 (d,J=10.07 Hz, 1H), 3.66 (d, J=10.07 Hz, 1H), 3.18-3.27 (m, 1H), 3.03-3.14(m, 1H), 2.94 (t, J=7.63 Hz, 2H), 2.70-2.90 (m, 2H), 2.06-2.24 (m, 2H),1.57-1.87 (m, 3H). MS (LC/MS) R.T.=1.76; [M+H]⁺=259.25.

Example 20N-(4-(4-Methoxyphenyl)thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A:N-(5-(4-Methoxyphenyl)thiazol-2-yl)-1H-imidazole-1-carbothioamide

To 5-(4-methoxyphenyl)thiazol-2-amine (1.07 g, 5.19 mmol) inacetonitrile (30 mL) and tetrahydrofuran (5 mL) was addeddi(1H-imidazol-1-yl)methanethione (1.20 g, 6.74 mmol). The reaction wasstirred at 60° C. for 18 hours. The reaction was cooled to roomtemperature and the precipitate was filtered. The powder was washed withcold acetonitrile (2×15 mL) and dried to yieldN-(5-(4-methoxyphenyl)thiazol-2-yl)-1H-imidazole-1-carbothioamide (0.59g, 1.86 mmol, 35.9% yield) as a orange-brown powder. The product wastaken directly to the next step without any further characterization.

Step B:(3-Hydroxy-3-((3-(4-(4-methoxyphenyl)thiazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate

To N-(4-(4-methoxyphenyl)thiazol-2-yl)-1H-imidazole-1-carbothioamide(0.57 g, 1.82 mmol) in N,N-dimethylformamide (20 mL) was added(3-(aminomethyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(0.31 g, 1.82 mmol). The reaction was stirred at 60° C. for 4 hours. Thereaction was cooled and concentrated to yield crude product. The crudematerial was purified via flash chromatography (60-100% ethylacetate-hexane) yielding the first spot/fractions (TLC) as the product.The fractions were combined and concentrated in vacuo to yield(3-hydroxy-3-((3-(4-(4-methoxyphenyl)thiazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(0.6 g, 1.43 mmol, 79% yield) as a white powder. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 11.74 (s, 1H), 7.91 (d, J=8.55 Hz, 2H), 7.43 (s, 1H),6.97 (d, J=8.85 Hz, 2H), 5.50 (s, 1H), 3.62-3.98 (m, 5H), 2.70-3.10 (m,6H), 2.13 (s, 1H), 1.94 (s, 1H), 1.66-1.91 (m, 2H), 1.11-1.62 (m, 4H).MS (LC/MS) R.T.=3.54; [M+H]⁺=417.1.

Step C:(2-(4-(4-Methoxyphenyl)thiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate

To(3-hydroxy-3-((3-(4-(4-methoxyphenyl)thiazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(0.59 g, 1.41 mmol) in N,N-dimethylformamide (20 mL) was addedN,N′-diisopropylcarbodiimide (0.66 mL, 4.23 mmol). The reaction wasstirred at 70° C. for 24 hours. The solvent was removed in vacuo and theresidue was purified by flash chromatography (50-100% ethylacetate-hexanes), collecting the first component as the product, toyield(2-(4-(4-methoxyphenyl)thiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate(0.45 g, 1.17 mmol, 83% yield) as a white powder. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.65 (s, 1H), 7.89 (d, J=7.32 Hz, 2H), 7.15-7.43 (m, 1H),6.95 (d, J=8.85 Hz, 2H), 3.64-3.93 (m, 5H), 3.23-3.31 (m, J=1.53 Hz,1H), 3.09-3.21 (m, 1H), 2.99-3.09 (m, 1H), 2.79-2.97 (m, 3H), 2.25 (s,1H), 1.96-2.16 (m, 1H), 1.68-1.91 (m, 3H), 1.45 (s, 3H). MS (LC/MS)R.T.=2.80; [M+H−BH₃]⁺=371.1.

Step D:N-(4-(4-Methoxyphenyl)thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To(2-(4-(4-methoxyphenyl)thiazol-2-ylamino)-4H-1′-ammoniospiro[oxazole-5,3′-bicyclo[2.2.2]octane]-1′-yl)trihydroborate(0.41 g, 1.07 mmol) in acetone (9 mL) was added 3M HCl (0.36 mL, 1.07mmol). The reaction was stirred at room temperature for 4 hours. Thereaction was complete by TLC (lower spot). Ethyl acetate was added andthe aqueous layer was then separated. The aqueous layer was neutralizedwith 1N sodium hydroxide. The product was extracted with ethyl acetate(2×40 mL). The organics were combined, dried with magnesium sulfate,filtered, and concentrated in vacuo to afford racemicN-(4-(4-methoxyphenyl)thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.3 g, 0.77 mmol, 72.1% yield) as a white powder. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.56 (s, 1H), 7.77-8.00 (m, J=8.55 Hz, 2H), 7.27 (s, 1H),6.80-7.08 (m, 2H), 3.87 (d, J=9.77 Hz, 1H), 3.79 (s, 3H), 3.61 (d,J=9.77 Hz, 1H), 3.02 (s, 3H), 2.60-2.92 (m, 4H), 2.06 (s, 2H), 1.82-2.00(m, 1H), 1.39-1.70 (m, 3H). MS (LC/MS) R.T.=1.95; [M+H]⁺=371.2.

The enantiomers were separated using a Chiralpak AD-H (30×250 mm, 5 μm)column with a mobile phase consisting of 30% methanol (0.1% DEA) in CO₂.The wavelength was set at 220 nM. The separated peaks were concentratedin vacuo to yield white powders. The first peak off the column was(S)—N-(4-(4-methoxyphenyl)thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.035 g, 0.09 mmol, 22.87% yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.56(1H, br. s.), 7.86 (2H, d, J=8.55 Hz), 7.25 (1H, s), 6.93-6.96 (2H, m),3.86 (1H, d, J=9.77 Hz), 3.78 (3H, s), 3.60 (1H, d, J=9.46 Hz), 3.01(2H, s), 2.72-2.84 (2 H, m), 2.62-2.71 (2H, m), 2.05 (1H, br. s.), 1.91(1H, br. s.), 1.55-1.64 (2H, m), 1.44-1.52 (1H, m). MS (LC/MS)R.T.=2.03; [M+H]⁺=371.3. The second peak was(R)—N-(4-(4-methoxyphenyl)thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.055 g, 0.15 mmol, 35.9% yield). (21b, R-isomer): ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.58 (1H, br. s.), 7.87 (2H, d, J=8.55 Hz), 7.26 (1H, s),6.92-6.97 (2H, m), 3.86 (1H, d, J=9.77 Hz), 3.78 (3H, s), 3.60 (1H, d,J=9.77 Hz), 3.01 (2H, s), 2.73-2.85 (2H, m), 2.63-2.71 (2H, m), 2.05(1H, br. s.), 1.91 (1H, br. s.), 1.54-1.64 (2H, m), 1.43-1.53 (1H, m).MS (LC/MS) R.T.=2.03; [M+H]⁺=371.3.

Example 21(R)—N-(2-(4H-1′-Azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-ylamino)benzo[d]thiazol-6-yl)acetamide

Step A:(3-((Benzyloxycarbonylamino)methyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate

To(3-(aminomethyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(10 g, 47.0 mmol) in dichloromethane (150 mL) was added sodium carbonate(200 mL, 200 mmol) and benzyl chloroformate (9.5 mL, 66.5 mmol). Thereaction mixture was stirred at room temperature for 40 minutes.Dichloromethane and water were added and the aqueous layer was thenseparated and extracted again with dichloromethane (2×). The organiclayers were combined, dried over sodium sulfate, filtered andconcentrated. The residue was purified via flash chromatography (12-100%ethyl acetate-hexanes). The product fractions were combined andconcentrated to yield racemic(3-((benzyloxycarbonylamino)methyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(3 g, 9.86 mmol, 20.96% yield) as a clear oil. ¹H NMR (400 MHz, CDCl₃) δppm 7.30-7.43 (5H, m), 5.27 (1H, br. s.), 5.12 (2H, s), 3.36 (2H, d,J=6.04 Hz), 2.76-3.21 (6H, m), 2.21 (1H, br. s.), 1.97 (1H, br. s.),1.71-1.86 (2H, m).

The enantiomers were separated using a Chiralpak OJ-H (5×25) column witha mobile phase consisting of 20% acetonitrile/methanol (1:1) in CO₂. Thewavelength was set at 210 nM. The first peak off the column was(R)-(3-(aminomethyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(37.67 g, 123 mmol) as a colorless oil. Optical rotation: +28.2, c=2.9in chloroform. The second peak off the column was(S)-(3-((benzyloxycarbonylamino)methyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(46.82 g, 153 mmol) as a light amber oil. Optical rotation: −27.4, c=2.5in chloroform.

Step B: (S)-3-(Aminomethyl)quinuclidin-3-ol, 2HCl

A solution of(S)-(3-((benzyloxycarbonylamino)methyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate(20.5 g, 67 mmol) in acetone (120 mL) was cooled on an ice bath. 3MAqueous HCl (120 mL, 360 mmol) was added over 2 minutes. Vigorousbubbling was observed. After 10 minutes, the cold ice bath was removedand the mixture was allowed to warm to room temperature. After 20minutes, it was diluted with methanol (800 mL) and flushed withnitrogen. Palladium on carbon (2 g, 1.88 mmol) was added and thereaction was flushed with nitrogen and fitted with balloon of hydrogen.The reaction mixture was stirred at room temperature overnight. It wasthen flushed with nitrogen and filtered through a pad of Celite usingmethanol. The solvent was evaporated to yield a crude yellow solid. Thesolids were dissolved in water (25 mL), then ethanol (400 mL) was added.White crystals formed immediately. They were collected by filtration andwashed with ethanol, followed by ether. A white crystalline solid wasobtained, (S)-3-(aminomethyl)quinuclidin-3-ol, 2 HCl (10.7 g, 46.7 mmol,69.3% yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.93 (1H, br. s.), 8.24(3H, br. s.), 6.02 (1H, s), 3.26 (1H, d, J=13.43 Hz), 2.99-3.22 (5H, m),2.10-2.19 (2H, m), 1.81-1.90 (1H, m), 1.72-1.81 (1H, m), 1.60-1.72 (1H,m). Optical rotation: [α]²⁰ _(D)=−50.9° (c=6.4, water).

Step C:N-(2-(1H-Imidazole-1-carbothioamido)benzo[d]thiazol-6-yl)acetamide

To N-(2-aminobenzo[d]thiazol-6-yl)acetamide (4 g, 19.3 mmol) inacetonitrile (100 mL) was added di(1H-imidazol-1-yl)methanethione (3.44g, 19.30 mmol). The reaction was allowed to stir at 80° C. overnight.The reaction was cooled to room temperature and the precipitate wasfiltered. The product,N-(2-(1H-imidazole-1-carbothioamido)benzo[d]thiazol-6-yl)acetamide (3.6g, 11.34 mmol, 58.85 yield), was taken directly to the next step withoutany further purification.

Step D:(R)—N-(2-(4H-1′-Azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]-2-ylamino)benzo[d]thiazol-6-yl)acetamide

To N-(2-(1H-imidazole-1-carbothioamido)benzo[d]thiazol-6-yl)acetamide(300 mg, 0.95 mmol) in N,N-dimethylformamide (10 mL) was added(S)-3-(aminomethyl)quinuclidin-3-ol, 2 HCl (238 mg, 1 mmol) andtriethylamine (0.39 mL, 2.84 mmol). The reaction was heated to 80° C.for 3 hours. N,N′-diisopropylcarbodiimide (0.59 mL, 3.78 mmol) was thenadded to the reaction mixture. The mixture was heated at 80° C. foranother 2 hours. The reaction was cooled, then chloroform and water wereadded to the mixture. The organic layer concentrated in vacuo to yieldcrude product. The crude material was purified via flash chromatography(2-20% [10% ammonium hydroxide/methanol-chloroform). The productfractions were then triturated with ether to yield(R)—N-(2-(4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]-2-ylamino)benzo[d]thiazol-6-yl)acetamide(144.5 mg, 0.39 mmol, 41.2% yield) as a white solid. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 9.98 (1H, s), 8.93 (1H, br. s.), 8.12 (1H, d, J=1.83 Hz),7.52 (1H, d, J=8.42 Hz), 7.38 (1H, dd, J=8.60, 2.01 Hz), 3.88 (1H, d,J=9.88 Hz), 3.62 (1H, d, J=9.88 Hz), 3.02 (2H, s), 2.74-2.85 (2H, m),2.66 (2H, t, J=7.68 Hz), 2.05 (4H, s), 1.91 (1H, br. s.), 1.41-1.64 (3H,m). MS (LC/MS) R.T.=1.55; [M+H]⁺=372.2.

Example 22(R)—N-(6-(Difluoromethoxy)benzo[d]thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 6-(Difluoromethoxy)benzo[d]thiazol-2-amine

To 4-(difluoromethoxy)aniline (9.55 g, 60 mmol) in acetic acid (90 mL)was added potassium thiocyanate (KSCN) (12.41 mL, 240 mmol). The mixturewas stirred for 20 minutes (KSCN dissolved into solution). To thismixture bromine (3.08 mL, 60.0 mmol) in acetic acid (40 mL) was addeddropwise over 20 minutes. The reaction was stirred at room temperatureovernight. It was poured into a mixture of 800 ml ice water and 200 mlsaturated ammonium hydroxide. The product was extracted with ethylacetate (5×). The organics were combined, washed with brine, dried oversodium sulfate, filtered and concentrated in vacuo to afford6-(difluoromethoxy)benzo[d]thiazol-2-amine (12.6 g, 52.4 mmol, 87%yield) as a yellow solid.

Step B:N-(6-(Difluoromethoxy)benzo[d]thiazol-2-yl)-1H-imidazole-1-carbothioamide

To 6-(difluoromethoxy)benzo[d]thiazol-2-amine (0.5 g, 2.3 mmol) inacetonitrile (15 mL) was added 1,1′-thiocarbonyldiimidazole (0.49 g, 2.8mmol). The reaction was stirred at 70° C. overnight. The reaction wascooled to room temperature and the precipitate was filtered to yieldN-(6-(difluoromethoxy)benzo[d]thiazol-2-yl)-1H-imidazole-1-carbothioamide(500 mg, 1.53 mmol, 66.3% yield) as a yellow solid.

Step C:(R)—N-(6-(Difluoromethoxy)benzo[d]thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To a solution ofN-(6-(difluoromethoxy)benzo[d]thiazol-2-yl)-1H-imidazole-1-carbothioamide(285 mg, 0.87 mmol) in N,N-dimethylformamide (5 mL) was added(S)-3-(aminomethyl)quinuclidin-3-ol, 2 HCl (200 mg, 0.87 mmol) andtriethylamine (0.4 mL, 2.87 mmol). The reaction was heated to 70° C. for2 hours. N,N′-diisopropylcarbodiimide (0.4 mL, 2.57 mmol) was then addedto the reaction mixture. The mixture was heated at 70° C. for another 3hours. It was cooled and then poured into toluene/0.3M sodium hydroxide.The product was extracted with toluene (4×) and chloroform (3×). Theorganics were combined, washed with water (3×), dried over sodiumsulfate, filtered and concentrated in vacuo to yield crude product. Thecrude material was purified via flash chromatography (2-20% [10%ammonium hydroxide/methanol]-chloroform) to afford(R)—N-(6-(difluoromethoxy)benzo[d]thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(186.2 mg, 0.49 mmol, 55.5% yield) as a white powder. M.P. 223-5° C. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 8.99 (1H, br. s.), 7.69 (1H, d, J=2.75 Hz),7.61 (1H, d, J=8.55 Hz), 7.02-7.34 (2H, m), 3.89 (1H, d, J=10.07 Hz),3.64 (1H, d, J=9.77 Hz), 3.03 (2H, d, J=2.44 Hz), 2.73-2.86 (2H, m),2.62-2.70 (2H, m), 2.07 (1H, br. s.), 1.92 (1H, br. s.), 1.54-1.65 (2H,m), 1.44-1.53 (1H, m). MS (LC/MS) R.T.=1.43; [M+H]⁺=381.1.

Step A: 4-Isothiocyanato-6-methoxypyrimidine

To a bright orange solution of 1,1′-thiocarbonyldipyridin-2(1H)-one(1.86 g, 7.99 mmol) in dichloromethane at room temperature was added6-methoxypyrimidin-4-amine (1 g, 8 mmol). The orange solution wasstirred at room temperature for 18 hours. The LC/MS showed the desiredproduct as one of the major peaks. The deep orange solution wasconcentrated and the remaining residue was filtered. The filtrate waspurified by silica gel chromatography (10-50% ethyl acetate/hexanes) toafford 4-isothiocyanato-6-methoxypyrimidine (0.72 g, 4.3 mmol, 54%yield) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.49 (1H, d,J=5.79 Hz), 6.95 (1H, d, J=5.79 Hz), 3.92 (3H, s). MS (LC/MS) R.T.=3.15;[M+H]⁺=168.1.

Step B:(R)—N-(6-Methoxypyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (from Step B ofExample 21) (0.34 g, 1.49 mmol) in N,N-dimethylformamide (15 mL) wasadded Cs₂CO₃ (1.22 g, 3.74 mmol) and4-isothiocyanato-6-methoxypyrimidine (0.25 g, 1.5 mmol). The suspensionwas stirred at room temperature for 30 minutes.N,N′-diisopropylcarbodiimide (0.7 mL, 4.5 mmol) was then added and themixture was stirred at room temperature for 18 hours. The mixture wasconcentrated and purified by silica gel chromatography (5-15% [9:1methanol:ammonium hydroxide]/chloroform) to afford(R)—N-(6-methoxypyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.21 g, 0.72 mmol, 48.2% yield) as a white solid. M.P. 186-8° C. ¹H NMR(400 MHz, MeOD) δ ppm 8.40 (1H, s), 6.17 (1H, br. s.), 3.92-4.04 (1H,m), 3.89 (3H, s), 3.68 (1H, d, J=10.32 Hz), 3.12-3.23 (1H, m), 2.98-3.12(1H, m), 2.67-2.97 (4H, m), 2.11 (2H, br. s.), 1.48-1.82 (3H, m). MS(LC/MS) R.T.=0.82; [M+H]⁺=290.3.

Example 24(R)—N-(6-Methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 5-Methoxypyridin-2-amine ethoxycarbonyl thiourea

To 5-methoxypyridin-2-amine (5 g, 40 mmol) in dioxane (40 mL) was addedethoxycarbonyl isothiocyanate (5.23 mL, 44.3 mmol). The reaction mixturewas stirred at room temperature overnight. The mixture was concentratedin vacuo to afford 5-methoxypyridin-2-amine ethoxycarbonyl thiourea(10.28 g, 40.3 mmol, 100% yield). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 12.03(1H, br. s.), 11.37 (1H, br. s.), 8.53 (1H, br. s.), 8.11 (1H, d, J=2.93Hz), 7.50 (1H, dd, J=8.97, 3.11 Hz), 4.22 (2H, q, J=7.07 Hz), 3.84 (3H,s), 1.26 (3H, t, J=7.14 Hz). MS (LC/MS) R.T.=2.40; [M+H]⁺=256.1.

Step B: 6-Methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-amine

To 5-methoxypyridin-2-amine ethoxycarbonyl thiourea (10.21 g, 40 mmol)in ethanol (57 mL) and methanol (57 mL) was added hydroxylaminehydrochloride (14 g, 200 mmol) and Hunig's Base (21 mL, 120 mmol). Themixture was stirred at room temperature for 2 hours, and then heated at60° C. for 4 hours. The reaction was cooled to room temperature andfiltered to remove solids. It was concentrated in vacuo and thensuspended in chloroform. The solids were filtered off to yield6-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-amine (6.05 g, 33.2 mmol, 83%yield). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.30 (1H, d, J=1.83 Hz),7.24-7.32 (1H, m), 7.16-7.23 (1H, m), 5.82 (2H, br. s.), 3.78 (3H, s).MS (LC/MS) R.T.=0.53; [M+H]⁺=165.2.

Two grams of 6-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-amine werepurified via flash chromatography (2-20% [10% ammoniumhydroxide/methanol]/chloroform) to afford6-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-amine (1.35 g, 8.22 mmol,67.5% yield). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.29 (1H, d, J=2.20 Hz),7.24-7.30 (1H, m), 7.15-7.22 (1H, m), 5.79 (2H, s), 3.78 (3H, s).

Step C: 2-Isothiocyanato-6-methoxy-[1,2,4]triazolo[1,5-a]pyridine

To 6-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-amine (0.3 g, 1.8 mmol) indichloromethane (15 mL) was added 1,1′-thiocarbonyldi-2(1H)-pyridone(0.51 g, 2.2 mmol). The reaction was stirred at room temperatureovernight, concentrated in vacuo and purified via flash chromatographyyielding 2-isothiocyanato-6-methoxy-[1,2,4]triazolo[1,5-a]pyridine (166mg, 0.8 mmol, 44% yield) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ ppm8.03 (1H, d, J=2.20 Hz), 7.54 (1H, d, J=9.88 Hz), 7.34 (1H, dd, J=9.51,2.56 Hz), 3.88 (3H, s).

Step D:(R)—N-(6-Methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To 2-isothiocyanato-6-methoxy-[1,2,4]triazolo[1,5-a]pyridine (160 mg,0.78 mmol) in N,N-dimethylformamide (5 ml) was added(S)-3-(aminomethyl)quinuclidin-3-ol, 2 HCl (178 mg, 0.78 mmol) andtriethylamine (0.32 ml, 2.33 mmol). The reaction was stirred at 70° C.for 1 hour. N,N′-Diisopropylcarbodiimide (0.36 ml, 2.33 mmol) was thenadded to the reaction mixture. The mixture was heated at 70° C. for 4hours, then cooled and poured into aqueous sodiumbicarbonate/chloroform. The product was extracted (3×) with chloroform.The combined organics were washed with water (3×), dried over sodiumsulfate, filtered, and concentrated in vacuo, then purified via flashchromatography (2-20% [10% ammonium hydroxide:methanol]/chloroform) toyield(R)—N-(6-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-4H-1′-azaspiro-[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(114.5 mg, 0.33 mmol, 42% yield) as a white powder. ¹H NMR (500 MHz,CDCl₃) δ ppm 8.51 (1H, br. s.), 8.08 (1H, d, J=2.44 Hz), 7.35 (1H, d,J=9.77 Hz), 7.18 (1H, dd, J=9.46, 2.44 Hz), 3.92 (1H, d, J=8.85 Hz),3.84 (3H, s), 3.58 (1H, d, J=8.85 Hz), 3.36-3.41 (1H, m), 2.72-3.05 (4H,m), 2.18-2.26 (1H, m, J=13.26, 9.98, 3.66, 3.49, 3.49 Hz), 2.13 (1H, br.s.), 1.79 (1H, br. s.), 1.67-1.76 (1H, m, J=13.96, 9.84, 4.27, 4.27 Hz),1.45-1.63 (2H, m). MS (LC/MS) R.T.=0.86; [M+H]⁺=329.2.

Example 25(R)—N-(5-(Trifluoromethyl)pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 5-(Trifluoromethyl)pyrazin-2-amine

To an ice bath-cooled solution of 5,6-diaminopyrimidin-4-ol (18 g, 143mmol) in 3M sodium hydroxide (180 mL, 540 mmol), was added3,3-dibromo-1,1,1-trifluoropropan-2-one (25.2 g, 93 mmol). The reactionwas stirred for 3 days at ambient temperature. The solids were filtered,dissolved in 60% sulfuric acid (140 mL), and stirred at 135° C. for 8 h.The reaction was cooled, poured over ice and allowed to sit for 16hours. The solution was neutralized to pH 8 with conc. ammoniumhydroxide and extracted with ethyl acetate (5×100 mL), dried over sodiumsulfate, filtered and concentrated. The solid residue was recrystallizedfrom benzene/hexane to afford 5-(trifluoromethyl)pyrazin-2-amine (2.28g, 14 mmol, 15% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.32 (1H, s), 7.99(1H, d, J=1.26 Hz), 5.02 (2H, br. s.). MS (LC/MS) R.T.=1.56;[M+H]⁺=164.03.

Step B:(R)—N-(5-(Trifluoromethyl)pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(5-(trifluoromethyl)pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by following the general procedures of Example 23, StepsA-B and using 5-(trifluoromethyl)pyrazin-2-amine (from Step A above) asthe starting material. ¹H NMR (400 MHz, CDCl₃) δ ppm 9.08 (1H, br. s.),8.35 (1H, s), 8.32 (1H, s), 3.95 (1H, d, J=9.57 Hz), 3.61 (1H, d, J=9.57Hz), 3.30 (1H, dd, J=14.86, 1.76 Hz), 2.65-2.99 (5H, m), 2.05-2.16 (2H,m), 1.64-1.74 (1H, m), 1.42-1.57 (2H, m). MS (LC/MS) R.T.=1.06;[M+H]⁺=328.30.

Example 26(R)—N-(6-Fluoro-1H-indazol-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 6-Fluoro-1H-indazol-3-amine

To 2,4-difluorobenzonitrile (1.21 g, 8.70 mmol) was added hydrazinemonohydrate (8.46 mL, 174 mmol). The mixture was heated to reflux for 5hours and then poured onto ice. The solution was extracted with ethylacetate, dried with magnesium sulfate, filtered and concentrated. Theresidue was purified by column chromatography (25-100% ethylacetate/hexane) to afford 6-fluoro-1H-indazol-3-amine (0.5 g, 3.3 mmol,38% yield) as light yellow powder. ¹H NMR (500 MHz, DMSO-D6) δ ppm 11.42(s, 1H), 7.70 (dd, J=8.55, 5.49 Hz, 1H), 6.97 (dd, J=10.07, 1.83 Hz,1H), 6.72-6.79 (m, 1H), 5.40 (s, 2H). MS (LC/MS) R.T.=0.61;[M+H]⁺=152.11.

Step B: 6-Fluoro-3-isothiocyanato-1H-indazole

To 6-fluoro-1H-indazol-3-amine (0.32 g, 2.1 mmol) in dichloromethane (15mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one (0.53 g, 2.30 mmol).The reaction was stirred at 50° C. for 3 hours. The reaction was cooledto room temperature and the crude product was purified by columnchromatography (25% ethyl acetate/hexanes) to afford6-fluoro-3-isothiocyanato-1H-indazole (0.30 g, 1.53 mmol, 73.0% yield)as a light yellow powder. ¹H NMR (500 MHz, DMSO-D6) δ ppm 13.39 (s, 1H),7.78 (dd, J=8.85, 4.88 Hz, 1H), 7.41 (dd, J=9.31, 1.68 Hz, 1H), 7.14(td, J=9.16, 1.83 Hz, 1H). MS (LC/MS) R.T.=3.69; [M+H]⁺=194.07.

Step C:(R)—N-(6-Fluoro-1H-indazol-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To 6-fluoro-3-isothiocyanato-1H-indazole (0.20 g, 1.04 mmol) in DMF (15mL) was added triethylamine (0.43 mL, 3.11 mmol) and(S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.26 g, 1.14 mmol)at room temperature. The reaction was stirred at 70° C. for 2 hours. Thereaction was cooled to room temperature and treated withN,N′-diisopropylcarbodiimide (0.48 mL, 3.11 mmol). The reaction was thenheated to 70° C. for 2 hours. The reaction was cooled to ambienttemperature and concentrated. The crude product was purified by columnchromatography (85% chloroform, 14% methanol, 1% ammonium hydroxide) toafford(R)—N-(6-fluoro-1H-indazol-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.22 g, 0.66 mmol, 64% yield) as a white powder. ¹H NMR (500 MHz,DMSO-D6) δ ppm 12.16 (s, 1H), 8.00 (s, 1H), 7.59-7.67 (m, 1H), 7.09 (dd,J=9.77, 2.14 Hz, 1H), 6.81-6.88 (m, 1H), 3.81 (d, J=9.16 Hz, 1H), 3.56(d, J=8.85 Hz, 1H), 3.00 (s, 2H), 2.78 (s, 2H), 2.67 (t, J=7.32 Hz, 2H),2.01 (d, J=2.44 Hz, 1H), 1.92 (s, 1H), 1.59 (d, J=5.80 Hz, 2H), 1.46 (s,1H). MS (LC/MS) R.T.=1.44; [M+H]⁺=316.16.

Example 27(R)—N-(Furo[3,2-c]pyridin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: Furo[3,2-c]pyridin-4-amine

To 4-chlorofuro[3,2-c]pyridine (1 g, 6.5 mmol) in toluene under nitrogenwas added racemic BINAP (0.243 g, 0.4 mmol), Pd₂(dba)₃ (0.12 g, 0.13mmol) and sodium tert-butoxide (0.88 g, 9.1 mmol). Benzophenoneimine(1.3 mL, 7.81 mmol) was added and the mixture was heated to 80° C. for 3h and cooled to room temperature. The reaction mixture was diluted withether, filtered through Celite, and washed with ether. The filtrate wasconcentrated and the deep orange residue was taken up in methanol (90ml) and treated with hydroxylamine (1.2 mL, 19.5 mmol). The mixture wasstirred at ambient temperature for 18 h and concentrated. The residuewas purified by column chromatography (95-100% ethyl acetate/hexanes) toafford furo[3,2-c]pyridin-4-amine (776 mg, 5.79 mmol, 89% yield) as adeep orange solid. MS (LC/MS) R.T.=0.51; [M+H]⁺=135.02.

Step B:(R)—N-(Furo[3,2-c]pyridin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(Furo[3,2-c]pyridin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by following the general procedures of Example 23, StepsA-B using furo[3,2-c]pyridin-4-amine (Step A above) as the startingmaterial. ¹H NMR (400 MHz, MeOD) δ ppm 8.08 (1H, d, J=5.79 Hz), 7.69(1H, d, J=2.01 Hz), 6.99-7.13 (2H, m), 4.00 (1H, d, J=10.07 Hz), 3.69(1H, d, J=10.07 Hz), 3.19-3.26 (1H, m), 3.05-3.13 (1H, m), 2.93 (2H, t,J=7.43 Hz), 2.73-2.87 (2H, m), 2.08-2.24 (2H, m), 1.52-1.82 (3H, m). MS(LC/MS) R.T.=0.68; [M+H]⁺=299.19.

Example 28(R)—N-(5-Phenylpyridin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 5-Phenylpyridin-3-amine

A mixture of 5-bromopyridin-3-amine (248 mg, 1.43 mmol), Pd(PPh₃)₄ (50.4mg, 0.04 mmol), toluene (3 mL), sodium carbonate (2 M, 3 mL, 6 mmol),and phenylboronic acid (195 mg, 1.60 mmol) dissolved in ethanol (3 mL)was heated for 4 hours in an oil bath at 90° C. and allowed to cool toroom temperature for 16 hours. The reaction mixture was transferred to aseparatory funnel and partitioned between ethyl acetate and water. Theaqueous phase was washed once more with ethyl acetate, and the combinedorganic phases were washed with brine and dried over magnesium sulfate,filtered and concentrated in vacuo. The residue was purified by columnchromatography (80% ethyl acetate/hexanes) to afford5-phenylpyridin-3-amine (31.9 mg, 0.19 mmol, 13% yield) as a whitesolid. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.17-8.42 (m, 1H), 8.02-8.20 (m,1H), 7.32-7.62 (m, 4H), 7.25 (s, 1H), 7.06-7.20 (m, 1H). MS (LC/MS)R.T.=0.91; [M+H]⁺=171.09.

Step B:(R)—N-(5-Phenylpyridin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(5-Phenylpyridin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by following the general procedures of Example 23, StepsA-B using 5-phenylpyridin-3-amine (from Step A above) as the startingmaterial. ¹H NMR (500 MHz, MeOD-d₄) δ ppm 8.40 (br. s., 2H), 7.66 (d,J=7.32 Hz, 2H), 7.46-7.56 (m, 3H), 7.43 (d, J=7.32 Hz, 1H), 3.79-4.02(m, 1H), 3.51-3.68 (m, 1H), 3.22 (d, J=14.95 Hz, 1H), 3.02-3.15 (m, 1H),2.72-2.99 (m, 3H), 2.14 (br. s., 2H), 1.76 (dd, J=9.31, 4.12 Hz, 3H),1.12-1.35 (m, 1H). MS (LC/MS) R.T.=0.90; [M+H]⁺=335.17.

Example 29(R)—N-(2-Phenylpyridin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(2-Phenylpyridin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared from 2-bromopyridin-4-amine by following the generalprocedures of Example 28, Steps A-B. ¹H NMR (500 MHz, MeOD) δ ppm 8.38(d, J=5.49 Hz, 1H), 7.88 (d, J=7.93 Hz, 2H), 7.71-7.84 (m, 1H), 7.48 (d,J=7.63 Hz, 3H), 7.19-7.36 (m, 1H), 3.94-4.09 (m, 1H), 3.61-3.79 (m, 1H),3.17-3.27 (m, 1H), 3.00-3.14 (m, 1H), 2.74-3.00 (m, 4H), 2.05-2.23 (m,2H), 1.55-1.86 (m, 3H). MS (LC/MS) R.T.=0.86; [M+H]⁺=335.23.

Example 30(R)—N-(6-Phenylpyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(6-Phenylpyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared from 6-bromopyridin-2-amine by following the generalprocedures of Example 28, Steps A-B. ¹H NMR (500 MHz, MeOD-d₄) δ ppm7.91 (d, J=7.63 Hz, 2H), 7.71 (t, J=7.78 Hz, 1H), 7.32-7.55 (m, 5H),4.04 (d, J=10.07 Hz, 1H), 3.72 (d, J=9.77 Hz, 1H), 3.23 (d, J=1.22 Hz,1H), 3.12 (s, 1H), 2.95 (s, 2H), 2.84 (s, 2H), 2.16 (br. s., 2H),1.58-1.85 (m, 3H). MS (LC/MS) R.T.=0.75; [M+H]⁺=335.23.

Example 31(R)—N-(6-(Difluoromethoxy)-1-methyl-1H-indazol-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 6-(Difluoromethoxy)-1-methyl-1H-indazol-3-amine

To 4-(difluoromethoxy)-2-fluorobenzonitrile (1 g, 5.3 mmol) was addedmethylhydrazine (4.92 g, 107 mmol). The mixture was heated to 50° C. for5 hours and then cooled to room temperature. The crude product waspurified by column chromatography (40-100% ethyl acetate/hexanes) toafford 6-(difluoromethoxy)-1-methyl-1H-indazol-3-amine (0.5 g, 2.35mmol, 44% yield) as a white powder. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.70(d, J=8.55 Hz, 1H), 7.14 (s, 1H), 6.73 (d, J=8.55 Hz, 1H), 5.49 (s, 1H),3.70 (s, 3H).

Step B:(R)—N-(6-(Difluoromethoxy)-1-methyl-1H-indazol-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(6-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by following the general procedures of Example 23, StepsA-B using 6-(difluoromethoxy)-1-methyl-1H-indazol-3-amine (Step A) asthe starting material. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.64 (d, J=8.55Hz, 1H), 7.28 (d, J=5.19 Hz, 1H), 6.83 (dd, J=8.55, 1.83 Hz, 1H), 3.88(s, 3H), 3.77-3.84 (m, 1H), 3.51-3.64 (m, 1H), 3.00 (s, 2H), 2.72-2.84(m, 2H), 2.67 (t, J=7.48 Hz, 2H), 2.02 (br. s., 1H), 1.85-1.98 (m, 1H),1.59 (d, J=5.80 Hz, 2H), 1.36-1.53 (m, 1H), 1.09 (d, J=6.41 Hz, 1H). MS(LC/MS) R.T.=1.04; [M+H]⁺=378.19.

Example 32(R)—N-(5-(Difluoromethoxy)thiazolo[5,4-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 2-(Difluoromethoxy)-5-nitropyridine

To 2-hydroxy-5-nitropyridine (7 g, 50 mmol) in acetonitrile (500 mL) wasadded sodium sulfate (1.5 g, 10.6 mmol), and2,2-difluoro-2-(fluorosulfonyl)acetic acid (6.2 mL, 60 mmol) and thereaction was allowed to stir at room temperature for 16 hours. Thereaction was quenched with saturated aqueous sodium bicarbonate and theacetonitrile was removed in vacuo. The remaining aqueous component wasextracted with ethyl acetate, washed with brine, dried over sodiumsulfate, filtered and concentrated in vacuo. The pale brown oily solidwas triturated with ether/hexanes, filtered and the filtrateconcentrated to afford 2-(difluoromethoxy)-5-nitropyridine (4.7 g, 24.7mmol, 49% yield) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.14(d, J=2.76 Hz, 1H), 8.68 (dd, J=9.03, 2.76 Hz, 1H), 7.98 (s, 0.5H), 7.62(s, 0.5H), 7.34 (d, J=9.03 Hz, 1H).

Step B: 6-(Difluoromethoxy)pyridin-3-amine

To 2-(difluoromethoxy)-5-nitropyridine (4.7 g, 24.7 mmol) in degassedmethanol (100 mL) was added 10% palladium on carbon (500 mg, 0.47 mmol)and the reaction was hydrogenated at atmospheric pressure for 1 hour. Tothis was added acetic acid (2.83 mL, 49.4 mmol) and the reaction wasfiltered through Celite and concentrated in vacuo to afford6-(difluoromethoxy)pyridin-3-amine (6.33 g, 25.9 mmol, 105% yield) as anolive green liquid. ¹H NMR (400 MHz, MeOD-d₄) δ ppm 7.60 (d, J=2.76 Hz,1H), 7.37 (s, 0.5H), 7.15 (dd, J=8.66, 2.89 Hz, 1H), 7.00 (s, 0.5H),6.71 (d, J=8.78 Hz, 1H).

Step C: 5-(Difluoromethoxy)thiazolo[5,4-b]pyridin-2-amine

To acetic acid (10 mL) cooled in an ice bath was added potassiumthiocyanate (3.18 g, 32.8 mmol) and 6-(difluoromethoxy)pyridin-3-amine(1 g, 4.1 mmol). The reaction was cooled in an ice-salt bath until thereaction temperature reached <0° C. A solution of bromine (0.65 mL, 12.7mmol) in acetic acid (3 mL) was added dropwise over 2 hours at a ratethat maintained the reaction temperature <0° C. This gave a very thickmixture. After the addition was complete, the mixture was left to stirand allowed to slowly warm to room temperature overnight. After stirringovernight, water (5 mL) was added and the mixture was heated to 85° C.in an oil bath. This mixture was then filtered while still hot. Theyellow filter cake was returned to the reaction flask, and an additional5 mL acetic acid was added. The mixture was heated again to 85° C., andthen filtered while still hot. The combined filtrates were cooled in anice bath and neutralized to pH 8 with concentrated ammonium hydroxide. Ayellow precipitate formed which was then collected by filtration. Thiscrude material was purified by column chromatography (12-100% ethylacetate/hexanes) to afford5-(difluoromethoxy)thiazolo[5,4-b]pyridin-2-amine (321 mg, 1.48 mmol,36.1% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.64-7.81 (m, 2H), 6.92 (d, J=8.53 Hz, 1H). MS (LC/MS) R.T.=1.66;[M+H]⁺=218.10.

Step D:N-(5-(Difluoromethoxy)thiazolo[5,4-b]pyridin-2-yl)-1H-imidazole-1-carbothioamide

5-(Difluoromethoxy)thiazolo[5,4-b]pyridin-2-amine (310 mg, 1.43 mmol)and di(1H-imidazol-1-yl)methanethione (311 mg, 1.75 mmol) were dissolvedin acetonitrile (5 mL) and heated to 70° C. in a sealed vial for 10hours. The vial was then stored in the freezer for 16 hours. The solidswere collected by filtration and washed with acetonitrile to affordN-(5-(difluoromethoxy)thiazolo[5,4-b]pyridin-2-yl)-¹H-imidazole-1-carbothioamide(296 mg, 0.72 mmol, 51% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.77 (d,J=4.77 Hz, 1H), 8.06 (d, J=8.53 Hz, 1H), 8.01 (s, 1H), 7.72 (s, 1H),7.54 (s, 1H), 6.94-7.13 (m, 1H).

Step E:(R)—N-(5-(Difluoromethoxy)thiazolo[5,4-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

ToN-(5-(difluoromethoxy)thiazolo[5,4-b]pyridin-2-yl)-1H-imidazole-1-carbothioamide(296 mg, 0.72 mmol) in N,N-dimethylformamide (4 mL) in a sealed vial wasadded (S)-3-(aminomethyl)quinuclidin-3-ol, 2 HCl (175 mg, 0.76 mmol) andtriethylamine (0.3 ml, 2.2 mmol) and the mixture was heated to 70° C.overnight.

To this was added N,N′-diisopropylcarbodiimide (350 μl, 2.25 mmol) andthe reaction was heated to 70° C. for 6 hours. It was cooled to ambienttemperature and poured into water/chloroform, extracted with additionalchloroform and concentrated in vacuo. The residue was then taken up intoluene and washed with water to remove the residualN,N-dimethylformamide. The residue was purified by column chromatography(2%-20% (10% ammonium hydroxide/methanol)/chloroform) to afford(R)—N-(5-(difluoromethoxy)thiazolo[5,4-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(104 mg, 0.27 mmol, 37% yield) as a pale cream colored solid. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 7.99 (d, J=8.78 Hz, 1H), 7.68 (s, 1H), 7.03 (d,J=8.53 Hz, 1H), 3.87 (d, J=10.04 Hz, 1H), 3.62 (d, J=10.04 Hz, 1H), 3.03(d, J=5.02 Hz, 2H), 2.80 (d, J=9.03 Hz, 2H), 2.65 (t, J=7.65 Hz, 2H),2.08 (br. s., 1H), 1.83-1.99 (m, 1H), 1.43-1.68 (m, 3H). MS (LC/MS)R.T.=1.73; [M+H]⁺=382.20.

Example 33(R)—N-(6-Isopropoxybenzo[d]thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(6-Isopropoxybenzo[d]thiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared from 4-isopropoxyaniline by following the generalprocedures of Example 32, Steps C-E. ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.49 (d, J=8.78 Hz, 1H), 7.38 (d, J=2.51 Hz, 1H), 6.90 (dd, J=8.78, 2.51Hz, 1H), 4.50-4.68 (m, 1H), 3.87 (d, J=10.04 Hz, 1H), 3.62 (d, J=9.79Hz, 1H), 2.79 (d, J=9.03 Hz, 2H), 2.66 (t, J=7.78 Hz, 2H), 2.06 (br. s.,1H), 1.85-1.96 (m, 1H), 1.42-1.67 (m, 3H), 1.17-1.34 (m, 6H), 0.96-1.19(m, 2H).

Example 34(R)—N-(5-(Pyrrolidin-1-yl)pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 5-(Pyrrolidin-1-yl)pyrazin-2-amine

A mixture of 5-bromopyrazin-2-amine (1.2 g, 6.9 mmol) and pyrrolidine (4mL, 48 mmol) was microwaved at 180° C., 200 W for 2 h. The reaction wasdiluted into 125 mL ethyl acetate and extracted with water (3×50 mL) andbrine (50 mL). It was dried over sodium sulfate, filtered andconcentrated. The crude product was purified by column chromatography (0to 3% methanol/methylene chloride) to afford5-(pyrrolidin-1-yl)pyrazin-2-amine (495 mg, 3. mmol, 43.7% yield). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 7.52 (1H, d, J=1.51 Hz), 7.36 (1H, d,J=1.76 Hz), 5.21 (2H, s), 3.24-3.29 (4H, m), 1.90 (4H, ddd, J=6.48,3.53, 3.34 Hz). MS (LC/MS) R.T.=0.52; [M+H]⁺=165.29.

Step B:(R)—N-(5-(Pyrrolidin-1-yl)pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(5-(Pyrrolidin-1-yl)pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared from 5-(pyrrolidin-1-yl)pyrazin-2-amine by following thegeneral procedures of Example 23, Steps A-B. ¹H NMR (500 MHz, CDCl₃) δppm 8.51 (1H, br. s.), 8.02 (1H, s), 7.44 (1H, d, J=0.92 Hz), 3.84 (1H,d, J=9.16 Hz), 3.51 (1H, d, J=8.85 Hz), 3.39-3.45 (4H, m), 3.31 (1H, dd,J=14.80, 1.07 Hz), 2.69-3.04 (5H, m), 2.15-2.25 (1H, m), 2.09 (1H, br.s.), 1.98-2.02 (4H+HOD, m), 1.64-1.74 (1H, m), 1.42-1.61 (2H, m). MS(LC/MS) R.T.=0.76; [M+H]⁺=329.40.

Example 35(R)-1-(5-(4H-1′-Azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]-2-ylamino)pyrazin-2-yl)pyrrolidin-2-one

Step A: 1-(5-Aminopyrazin-2-yl)pyrrolidin-2-one

A mixture of 5-bromopyrazin-2-amine (5 g, 29 mmol), pyrrolidin-2-one (11mL, 144 mmol), copper (I) iodide (1.1 g, 5.75 mmol), potassium carbonate(7.94 g, 57.5 mmol), and (1R,2R)-cyclohexane-1,2-diamine (1.38 mL, 11.49mmol) was refluxed under nitrogen in dioxane (100 mL) for 18 h. Aftercooling, 200 mL ethyl acetate and 20 mL methanol were added to thereaction. This was filtered through celite, concentrated, and absorbedonto sodium sulfate for purification by column chromatography (0-5%methanol/methylene chloride). The purified product was recrystallizedfrom ether/ethyl acetate to afford1-(5-aminopyrazin-2-yl)pyrrolidin-2-one (1.57 g, 8.81 mmol, 30.7%yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.74 (1H, d, J=1.51 Hz), 7.69(1H, d, J=1.51 Hz), 6.20 (2H, s), 3.84 (2H, t, J=7.05 Hz), 2.49 (2H, t,J=7.93 Hz), 2.04 (2H, dq, J=7.68, 7.51 Hz). MS (LC/MS) R.T.=0.48;[M+H]⁺=179.27.

Step B:(R)-1-(5-(4H-1′-Azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-ylamino)pyrazin-2-yl)pyrrolidin-2-one

(R)-1-(5-(4H-1′-Azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]-2-ylamino)pyrazin-2-yl)pyrrolidin-2-onewas prepared from 1-(5-Aminopyrazin-2-yl)pyrrolidin-2-one by followingthe general procedures of Example 23, Steps A-B.

¹H NMR (500 MHz, CDCl₃) δ ppm 9.20 (1H, d, J=1.22 Hz), 8.91 (1H, br.s.), 8.13 (1H, s), 4.02 (2H, t, J=7.02 Hz), 3.92 (1H, d, J=9.46 Hz),3.58 (1H, d, J=9.16 Hz), 3.33 (1H, dd, J=14.95, 1.53 Hz), 2.71-3.01 (5H,m), 2.63 (2H, t, J=8.09 Hz), 2.08-2.23 (4H, m), 1.66-1.76 (1H, m),1.42-1.61 (2H, m). MS (LC/MS) R.T.=0.67; [M+H]⁺=343.30.

Example 36(R)—N-(5-(Pyridin-3-yl)pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 5-(Pyridin-3-yl)pyrazin-2-amine

Pyridin-3-ylboronic acid (307 mg, 2.50 mmol), 5-bromopyrazin-2-amine(391 mg, 2.25 mmol) and dichlorobis(triphenylphosphine)-palladium(II)(88 mg, 0.13 mmol) were added to degassed dioxane (12 mL) and themixture was stirred for 30 min. Then sodium carbonate (795 mg, 7.50mmol) and degassed water (8 mL) were added and the reaction was heatedin a closed reaction vial at 100° C. for 8 h. The reaction was allowedto stand at ambient temperature over the weekend. It was diluted intoethyl acetate (100 mL) and extracted with brine (3×25 mL). The organiclayers were dried over sodium sulfate and concentrated in vacuo. Thecrude product was purified by column chromatography (0 to 5%methanol/ethyl acetate) to afford 5-(pyridin-3-yl)pyrazin-2-amine (235mg, 1.37 mmol, 54.6% yield). ¹H NMR (400 MHz, Acetone) δ ppm 9.13 (1H,d, J=1.51 Hz), 8.54 (1H, d, J=1.26 Hz), 8.50 (1H, dd, J=4.78, 1.51 Hz),8.22-8.28 (1H, m), 8.07 (1H, d, J=1.26 Hz), 7.39 (1H, ddd, J=7.87, 4.72,0.76 Hz), 6.05 (2H, br. s.). MS (LC/MS) R.T.=0.58; [M+H]⁺=173.20.

Step B:(R)—N-(5-(Pyridin-3-yl)pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(5-(Pyridin-3-yl)pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared from 5-(pyridin-3-yl)pyrazin-2-amine by following thegeneral procedures of Example 23, Steps A-B. ¹H NMR (400 MHz, CDCl₃) δppm 9.12 (1H, dd, J=2.27, 0.76 Hz), 9.08 (1H, br. s.), 8.59 (1H, dd,J=4.78, 1.76 Hz), 8.55 (1H, d, J=1.51 Hz), 8.45 (1H, d, J=1.26 Hz), 8.25(1H, dt, J=7.99, 1.92 Hz), 7.38 (1H, ddd, J=8.06, 4.78, 0.76 Hz), 3.97(1H, d, J=9.57 Hz), 3.63 (1H, d, J=9.32 Hz), 3.36 (1H, dd, J=14.86, 1.76Hz), 2.69-3.06 (5H, m), 2.14-2.24 (1H, m), 2.12 (1H, br. s.), 1.66-1.77(1H, m, J=13.94, 9.66, 4.31, 4.31 Hz), 1.44-1.62 (2H, m). MS (LC/MS)R.T.=0.65; [M+H]⁺=337.30.

Example 37(R)—N-(5-(6-Methoxypyridin-3-yl)pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(5-(6-Methoxypyridin-3-yl)pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared from 5-bromopyrazin-2-amine by following the generalprocedures of Example 36, Steps A-B. ¹H NMR (400 MHz, CDCl₃) δ ppm 9.04(1H, br. s.), 8.66 (1H, d, J=2.01 Hz), 8.46 (1H, d, J=1.51 Hz), 8.41(1H, d, J=1.01 Hz), 8.15 (1H, dd, J=8.81, 2.52 Hz), 6.82 (1H, d, J=8.31Hz), 3.97 (3H, s), 3.95 (1H, d, J=9.57 Hz), 3.61 (1H, d, J=9.32 Hz),3.35 (1H, dd, J=14.86, 1.51 Hz), 2.68-3.07 (5H, m), 2.14-2.24 (1H, m,J=13.27, 9.93, 3.53, 3.38, 3.38 Hz), 2.11 (1H, br. s.), 1.67-1.77 (1H,m), 1.45-1.61 (2H, m). MS (LC/MS) R.T.=0.81; [M+H]⁺=367.40.

Example 38(R)—N-(6-Methoxyquinoxalin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 7-Methoxyquinoxalin-2(1H)-one and 6-methoxyquinoxalin-2(1H)-one

A 50% solution of ethyl 2-oxoacetate (18.47 mL, 93 mmol) in toluene wasadded to a solution of 4-methoxybenzene-1,2-diamine (10.73 g, 78 mmol)in ethanol (100 mL) at ambient temperature and the reaction was refluxedfor 2 h. The reaction was concentrated in vacuo and crystallized fromethanol to afford a mixture of 6-methoxyquinoxalin-2(1H)-one and7-methoxyquinoxalin-2(1H)-one (5.73 g, 32.50 mmol, 42% yield). MS(LC/MS) R.T.=0.68; [M+H]⁺=177.10.

Step B: 2-Chloro-6-methoxyquinoxaline

A mixture of 6-methoxyquinoxalin-2(1H)-one and7-methoxyquinoxalin-2(1H)-one (5.67 g, 32.20 mmol) was refluxed inphosphorus oxychloride (120 mL) for 1 h. The reaction was concentratedand quenched by addition of ice, then basified with sodium carbonate,and extracted with ethyl acetate (3×200 mL). The organic layers werecombined and concentrated in vacuo. The crude product was absorbed ontosodium sulfate and purified by column chromatography (0 to 5% ethylacetate/hexanes) to afford 2-chloro-6-methoxyquinoxaline (2.21 g, 11.36mmol, 35% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.69 (s, 1H), 7.88 (d,J=9.32 Hz, 1H), 7.43 (dd, J=9.32, 2.77 Hz, 1H), 7.37 (d, J=2.77 Hz, 1H),3.95 (s, 3H).

Step C: N-(2,4-Dimethoxybenzyl)-6-methoxyquinoxalin-2-amine

2-Chloro-6-methoxyquinoxaline (0.93 g, 4.77 mmol) and(2,4-dimethoxyphenyl)methanamine (2.2 ml, 14.64 mmol) were microwaved indimethylsulfoxide (5 mL) for 30 min at 150° C. The reaction was dilutedinto ethyl acetate (250 mL) and extracted with brine (3×100 mL). Thecrude product was purified by column chromatography (20 to 80% ethylacetate/hexanes) to affordN-(2,4-dimethoxybenzyl)-6-methoxyquinoxalin-2-amine (1.46 g, 87% yield).¹H NMR (400 MHz, CDCl₃) δ ppm 8.13 (1H, s), 7.59-7.63 (1H, m), 7.30 (1H,d, J=8.31 Hz), 7.21-7.24 (2H, m), 6.47 (1H, d, J=2.27 Hz), 6.42 (1H, dd,J=8.31, 2.27 Hz), 5.10 (1H, t, J=5.92 Hz), 4.61 (2H, d, J=5.79 Hz), 3.88(3H, s), 3.84 (3H, s), 3.78 (3H, s). MS (LC/MS) R.T.=1.95;[M+H]⁺=326.23.

Step D: 6-Methoxyquinoxalin-2-amine

N-(2,4-Dimethoxybenzyl)-6-methoxyquinoxalin-2-amine (2.8 g, 8.61 mmol)was stirred in TFA (10 mL, 130 mmol) and dichloromethane (10 mL) atambient temperature for 30 min. The solvents were removed in vacuo.Saturated aq. sodium hydrogen carbonate (200 mL) was added to the redresidue, which then precipitated a yellow solid. The mixture wasextracted extensively with dichloromethane. The organic layer was driedover sodium sulfate, filtered and concentrated in vacuo to afford6-methoxyquinoxalin-2-amine (1.50 g, 8.56 mmol, 99% yield). ¹H NMR (400MHz, CDCl₃) δ ppm 8.27 (1H, s), 7.54-7.58 (1H, m), 7.25-7.29 (2H, m),4.71 (2H, br. s.), 3.90 (3H, s). MS (LC/MS) R.T.=0.86; [M+H]⁺=176.23.

Step E:(R)—N-(6-Methoxyquinoxalin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(6-Methoxyquinoxalin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared from 6-methoxyquinoxalin-2-amine by following the generalprocedures of Example 23, Steps A-B. ¹H NMR (400 MHz, CDCl₃) δ ppm 9.61(1H, br. s.), 8.57 (1H, s), 7.62 (1H, d, J=9.06 Hz), 7.23-7.32 (2H, m),4.01 (1H, d, J=9.32 Hz), 3.90 (3H, s), 3.66 (1H, d, J=9.32 Hz), 3.37(1H, dd, J=14.86, 1.51 Hz), 2.68-3.08 (5H, m), 2.15-2.25 (1H, m),2.10-2.14 (1H, m), 1.67-1.77 (1H, m), 1.42-1.63 (2H, m). MS (LC/MS)R.T.=0.81; [M+H]⁺=340.30.

Example 39(R)—N-(5-(Difluoromethoxy)pyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 2-Chloro-5-(Difluoromethoxy)pyrimidine

2-Chloropyrimidin-5-ol (1 g, 7.66 mmol) and sodium2-chloro-2,2-difluoroacetate (3.50 g, 22.98 mmol) inN,N-dimethylformamide (20 mL) and water (0.2 mL) were heated to 90° C.for 24 hours and concentrated in vacuo. The residue was purified bycolumn chromatography (5-30% ethyl acetate/hexanes) to afford2-chloro-5-(difluoromethoxy)pyrimidine (549 mg, 3.04 mmol, 39.7% yield)as a pale yellow oil. MS (LC/MS) R.T.=1.32; [M+H]⁺=181.14.

Step B:(R)—N-(5-(Difluoromethoxy)pyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(5-(Difluoromethoxy)pyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared from 2-chloro-5-(difluoromethoxy)pyrimidine by followingthe general procedures of Example 23, Steps A-B. ¹H NMR (400 MHz,MeO-d₄) δ ppm 8.46 (2H, s), 6.85 (1H, t), 4.02 (1H, d, J=10.07 Hz), 3.73(1H, d, J=10.32 Hz), 3.28 (1H, d, J=1.01 Hz), 3.16 (1H, d), 2.81-3.05(4H, m), 2.08-2.25 (2H, m), 1.46-1.89 (3H, m). MS (LC/MS) R.T.=0.53;[M+H]⁺=326.30.

Example 40(R)—N-(4,5-Dimethylpyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 4,5-Dimethylpyrimidin-2-amine

A solution of 4-chloro-5,6-dimethylpyrimidin-2-amine (0.35 g, 2.22 mmol)in 2M ammonia in methanol (100 ml) was flushed with nitrogen andpalladium on carbon (0.035 g, 0.33 mmol) was added, flushed withnitrogen and the reaction was hydrogenated at 1 atm, ambient temperaturefor 18 h. The reaction mixture was flushed with nitrogen and filteredthrough celite and the celite pad washed with methanol. The filtrate wasevaporated to dryness in vacuo to afford 4,5-dimethylpyrimidin-2-amine(0.35 g, 2.56 mmol, 90% yield) which was used without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.89 (1H, s), 6.19 (2H,s), 2.18 (3H, s), 1.99 (3H, s). MS (LC/MS) R.T.=0.56; [M+H]⁺=124.20.

Step B:(R)—N-(4,5-Dimethylpyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(4,5-Dimethylpyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared from 4,5-dimethylpyrimidin-2-amine by following the generalprocedures of Example 23, Steps A-B. ¹H NMR (400 MHz, MeOD-d₄) δ ppm8.22 (1H, s), 4.01 (1H, d, J=10.07 Hz), 3.73 (1H, d, J=10.32 Hz), 3.40(1H, d), 3.25 (1H, d), 2.91-3.12 (4H, m), 2.41 (3H, s), 2.09-2.28 (5H,m), 1.62-1.97 (3H, m). MS (LC/MS) R.T.=0.47; [M+H]⁺=288.31.

Example 41(R)—N-(6-Phenylpyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 6-Phenylpyrimidin-4-amine

A mixture of 6-chloropyrimidin-4-amine (0.32 g, 2.5 mmol), phenylboronicacid (0.38 g, 3.13 mmol), saturated aqueous sodium carbonate (0.80 g,7.50 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.035 g,0.05 mmol) were suspended in a mixture of dimethoxyethane (15mL)/ethanol (2 mL)/water (2 mL). The mixture was heated in the microwaveat 125° C. for 20 min then concentrated in vacuo. The residue waspurified by column chromatography (10-60% ethyl acetate/hexanes) toafford 6-phenylpyrimidin-4-amine (167 mg, 0.98 mmol, 39% yield) as anoff-white solid. MS (LC/MS) R.T.=0.99; [M+H]⁺=172.23.

Step B:(R)—N-(6-Phenylpyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(6-Phenylpyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared from 6-phenylpyrimidin-4-amine by following the generalprocedures of Example 23, Steps A-B. ¹H NMR (400 MHz, MeOD-d₄) δ ppm9.54 (1H, d, J=1.01 Hz), 8.75-8.86 (2H, m), 8.18-8.28 (3H, m), 8.00 (1H,br. s.), 4.70 (1H, d, J=10.32 Hz), 4.43 (1H, d, J=10.58 Hz), 3.72-3.88(2H, m), 3.41-3.63 (4H, m), 2.63-2.87 (2H, m), 2.18-2.48 (3H, m). MS(LC/MS) R.T.=1.36; [M+H]⁺=336.24.

Example 42(R)—N-(6-(4-Methoxyphenyl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(6-(4-Methoxyphenyl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared from 6-chloropyrimidin-4-amine by following the generalprocedures of Example 41, Steps A-B. ¹H NMR (400 MHz, MeOD-d₄) δ ppm8.72 (1H, d, J=1.26 Hz), 7.90-8.00 (2H, m), 7.16 (1H, br. s.), 6.96-7.05(2H, m), 4.04 (1H, d, J=10.07 Hz), 3.84 (3H, s), 3.73 (1H, d, J=10.07Hz), 3.22 (1H, d), 3.09 (1H, d), 2.73-2.98 (4H, m), 2.02-2.21 (2H, m),1.51-1.85 (3H, m). MS (LC/MS) R.T.=1.44; [M+H]⁺=366.28.

Example 43(R)—N-(6-(6-Methoxypyridin-3-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(6-(6-Methoxypyridin-3-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared from 6-chloropyrimidin-4-amine by following the generalprocedures of Example 41, Steps A-B. ¹H NMR (400 MHz, MeOD-d₄) δ ppm8.79 (2H, dd, J=19.01, 1.89 Hz), 8.27 (1H, dd, J=8.56, 2.52 Hz), 7.18(1H, br. s.), 6.89 (1H, d, J=8.81 Hz), 4.05 (1H, d, J=10.32 Hz), 3.96(3H, s), 3.74 (1H, d, J=10.32 Hz), 3.23 (1H, d), 3.10 (1H, d), 2.73-2.99(4H, m), 2.02-2.21 (2H, m), 1.53-1.84 (3H, m). MS (LC/MS) R.T.=1.34;[M+H]⁺=367.25.

Example 44(R)—N-(6-(Naphthalen-2-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(6-(Naphthalen-2-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared from 6-chloropyrimidin-4-amine by following the generalprocedures of Example 41, Steps A-B. ¹H NMR (400 MHz, MeOD-d₄) δ ppm8.83 (1H, s), 8.56 (1H, s), 7.83-8.13 (4H, m), 7.49-7.58 (2H, m), 7.37(1H, br. s.), 4.06 (1H, d, J=10.32 Hz), 3.76 (1H, d, J=10.32 Hz), 3.23(1H, s), 3.12 (1H, d), 2.75-3.00 (4H, m), 2.02-2.24 (2H, m), 1.56-1.84(3H, m). MS (LC/MS) R.T.=1.93; [M+H]⁺=386.31.

The compounds in Table 2 were synthesized according to the method ofExample 1 using the appropriate commercially available isothiocyanate oramine. Amide-containing intermediates were obtained by the proceduresdescribed in Example 3.

TABLE 2

Example LCMS RT LCMS Ion Number R₁ (min) [M + H]⁺ ¹H NMR 45

1.48 341.3 ¹H NMR (500 MHz, DMSO- d₆) δ ppm 8.60 (1 H, br. s.), 7.94 (2H, d, J = 7.63 Hz), 7.43 (1 H, s), 7.39 (2 H, t, J = 7.78 Hz), 7.28 (1H, t, J = 7.32 Hz), 3.86 (1 H, d, J = 9.77 Hz), 3.60 (1 H, d, J = 9.77Hz), 2.98- 3.06 (2 H, m), 2.71-2.85 (2 H, m), 2.66 (2 H, t, J = 7.78Hz), 2.05 (1 H, br. s.), 1.91 (1 H, br. s.), 1.53-1.64 (2 H, m), 1.48 (1H, td, J = 9.99, 7.78 Hz) 46

1.41 400.4 ¹H NMR (500 MHz, DMSO- d₆) δ ppm 8.86 (1 H, br. s.), 7.47 (1H, d, J = 8.85 Hz), 7.33 (1 H, d, J = 2.44 Hz), 7.01 (1 H, dd, J = 8.85,2.75 Hz), 3.87 (1 H, d, J = 10.07 Hz), 3.71- 3.77 (4 H, m), 3.61 (1 H,d, J = 9.77 Hz), 3.06-3.12 (4 H, m), 3.01 (2 H, s), 2.72-2.86 (2 H, m),2.66 (2 H, t, J = 7.63 Hz), 2.05 (1 H, br. s.), 1.91 (1 H, br. s.),1.53-1.64 (2 H, m), 1.43-1.52 (1 H, m) 47

1.31 333.3 ¹H NMR (500 MHz, DMSO- d₆) δ ppm 9.03 (1 H, br. s.), 7.80 (1H, dd, J = 8.70, 5.65 Hz), 7.37 (1 H, dd, J = 10.38, 2.44 Hz), 7.04 (1H, td, J = 9.08, 2.59 Hz), 3.89 (1 H, d, J = 10.07 Hz), 3.64 (1 H, d, J= 10.07 Hz), 3.03 (2 H, d, J = 2.75 Hz), 2.74-2.85 (2 H, m), 2.62-2.70(2 H, m), 2.07 (1 H, d, J = 2.44 Hz), 1.90 (1 H, d, J = 8.85 Hz),1.54-1.64 (2 H, m), 1.43-1.53 (1 H, m) 48

2.07 383.3 ¹H NMR (500 MHz, DMSO- d₆) δ ppm 8.00 (1 H, s), 7.41- 7.54 (2H, m), 3.89 (1 H, d, J = 11.29 Hz), 3.57 (1 H, d, J = 11.60 Hz),2.96-3.03 (1 H, m), 2.88-2.93 (1 H, m), 2.73- 2.81 (2 H, m), 2.64 (2 H,dd, J = 8.85, 5.19 Hz), 1.93 (2 H, br. s.), 1.56 (2 H, br. s.), 1.38-1.50 (1 H, m) 49

2.15 399.4 ¹H NMR (500 MHz, DMSO- d₆) δ ppm 9.03 (1 H, br. s.), 7.91 (1H, br. s.), 7.65 (1 H, d, J = 8.85 Hz), 7.30 (1 H, d, J = 7.63 Hz), 3.89(1 H, d, J = 10.07 Hz), 3.64 (1 H, d, J = 10.07 Hz), 2.97-3.09 (2 H, m),2.80 (2 H, d, J = 8.55 Hz), 2.66 (2 H, t, J = 7.48 Hz), 2.08 (1 H, br.s.), 1.93 (1 H, br. s.), 1.54-1.66 (2 H, m), 1.44- 1.54 (1 H, m) 50

1.89 333.1 ¹H NMR (500 MHz, MeOD) δ ppm 7.51-7.58 (1 H, m), 7.17-7.25(1H, m), 7.08- 7.16 (1 H, m), 4.04-4.13 (1 H, m), 3.72-3.82 (1 H, m),3.30 (1 H, br. s.), 3.17 (1 H, d, J = 14.95 Hz), 3.01 (2 H, t, J = 7.48Hz), 2.80-2.92 (2 H, m), 2.12-2.27 (2 H, m), 1.66-1.88 (3 H, m) 51

1.24 333.4 ¹H NMR (500 MHz, DMSO- d₆) δ ppm 8.95 (1 H, br. s.),7.66-7.77 (1 H, m), 7.52- 7.63 (1 H, m), 7.08-7.24 (1 H, m), 3.88 (1 H,d, J = 9.77 Hz), 3.63 (1 H, d, J = 9.77 Hz), 3.03 (2 H, br. s.), 2.78 (2H, br. s.), 2.66 (2 H, t, J = 7.17 Hz), 2.06 (1 H, br. s.), 1.91 (1 H,br. s.), 1.39-1.67 (3 H, m) 52

2.05 351.2 ¹H NMR (500 MHz, DMSO- d₆) δ ppm 9.01 (1 H, br. s.),7.88-8.00 (1H, m), 7.53- 7.64 (1 H, m), 3.88 (1 H, d, J = 10.07 Hz),3.63 (1 H, d, J = 10.07 Hz), 2.98-3.08 (2 H, m), 2.72-2.87 (2 H, m),2.66 (2 H, t, J = 7.17 Hz), 2.07 (1 H, br. s.), 1.92 (1 H, br. s.),1.42- 1.65 (3 H, m) 53

1.80 345.3 ¹H NMR (500 MHz, DMSO- d₆) δ ppm 9.03 (s, 1 H), 7.65 (d, J =8.55 Hz, 1 H), 7.19 (d, J = 2.44 Hz, 1 H), 6.82 (dd, J = 8.70, 2.59 Hz,1 H), 3.90 (d, J = 10.07 Hz, 1 H), 3.79 (s, 3 H), 3.64 (d, J = 10.07 Hz,1 H), 3.04 (d, J = 2.44 Hz, 2 H), 2.75-2.84 (m, 2 H), 2.67 (t, J = 7.78Hz, 2 H), 2.07 (s, 1 H), 1.92 (s, 1 H), 1.55-1.63 (m, 2 H), 1.49 (dd, J= 9.77, 2.75 Hz, 1 H) 54

1.23 345.2 ¹H NMR (500 MHz, DMSO- d₆) δ ppm 8.83 (s, 1 H), 7.37 (d, J =7.94 Hz, 1 H), 7.14 (t, J = 7.93 Hz, 1 H), 6.92 (d, J = 7.93 Hz, 1 H),3.89-3.95 (m, 4 H), 3.66 (d, J = 10.07 Hz, 1 H), 3.00-3.08 (m, 2 H),2.76-2.85 (m, 2 H), 2.67 (t, J = 7.78 Hz, 2 H), 2.08 (s, 1 H), 1.93 (d,J = 3.66 Hz, 1 H), 1.60 (ddd, J = 15.26, 6.87, 3.20 Hz, 2 H), 1.50 (ddd,J = 7.48, 5.19, 2.59 Hz, 1 H) 55

1.72 375.2 ¹H NMR (500 MHz, DMSO- d₆) δ ppm 8.89 (s, 1 H), 7.40 (s, 1H), 7.22 (s, 1 H), 3.87 (d, J = 10.07 Hz, 1 H), 3.79 (d, J = 8.55 Hz, 6H), 3.62 (d, J = 10.07 Hz, 1 H), 2.99-3.07 (m, 2 H), 2.75-2.84 (m, 2 H),2.67 (t, J = 7.63 Hz, 2 H), 2.06 (s, 1 H), 1.93 (s, 1 H), 1.56- 1.64 (m,2 H), 1.46-1.55 (m, 1 H) 56

2.14 342.1 ¹H NMR (500 MHz, DMSO- d₆) δ ppm 8.75 (s, 1 H), 7.84 (dd, J =7.93, 1.53 Hz, 3 H), 7.46-7.53 (m, 5 H), 3.85 (d, J = 9.77 Hz, 2 H),3.60 (d, J = 10.07 Hz, 2 H), 3.01-3.09 (m, 3 H), 2.84 (t, J = 7.78 Hz, 3H), 2.67 (t, J = 7.78 Hz, 3 H), 2.09 (s, 2 H), 1.91-1.99 (m, 2 H),1.53-1.62 (m, 3 H) 57

1.04 386.2 ¹H NMR (400 MHz, DMSO- d₆) δ ppm 9.05 (1 H, br. s.), 7.86 (1H, d, J = 1.51 Hz), 7.60 (1 H, d, J = 8.06 Hz), 7.36 (1 H, dd, J = 8.31,1.76 Hz), 3.90 (1 H, d, J = 10.07 Hz), 3.65 (1 H, d, J = 10.07 Hz), 3.03(2 H, s), 2.97 (6 H, s), 2.72-2.87 (2 H, m), 2.66 (2 H, t, J = 7.68 Hz),2.07 (1 H, br. s.), 1.92 (1 H, br. s.), 1.55-1.64 (2 H, m), 1.44-1.54 (1H, m) 58

1.57 426.2 ¹H NMR (400 MHz, DMSO- d₆) δ ppm 9.06 (1 H, br. s.), 7.83 (1H, d, J = 1.51 Hz), 7.61 (1 H, d, J = 8.31 Hz), 7.32 (1 H, dd, J = 8.31,1.76 Hz), 3.90 (1 H, d, J = 10.07 Hz), 3.65 (1 H, d, J = 10.07 Hz),3.37-3.57 (4 H, m), 3.04 (2 H, d, J = 1.76 Hz), 2.73-2.86 (2 H, m), 2.66(2 H, t, J = 7.68 Hz), 2.07 (1 H, d, J = 2.52 Hz), 1.92 (1 H, dd, J =8.18, 5.67 Hz), 1.43-1.67 (9 H, m) 59

2.17 360.1 ¹H NMR (500 MHz, DMSO- D6) δ ppm 8.74 (s, 1 H), 7.86- 7.92(m, 2 H), 7.31-7.37 (m, 2 H), 3.85 (d, J = 9.77 Hz, 1 H), 3.60 (d, J =9.77 Hz, 1 H), 3.00-3.09 (m, 2 H), 2.84 (t, J = 7.48 Hz, 2 H), 2.67 (t,J = 7.32 Hz, 2 H), 2.09 (d, J = 1.83 Hz, 1 H), 1.89-1.98 (m, 1 H),1.55-1.61 (m, 2 H), 1.51-1.54 (m, J = 11.29 Hz, 1 H) 60

1.67 332.2 ¹H NMR (500 MHz, DMSO- D6) δ ppm 7.87 (s, 1 H), 7.01 (d, J =3.05 Hz, 1 H), 6.68 (dd, J = 3.51, 1.68 Hz, 1 H), 3.84 (d, J = 10.38 Hz,1 H), 3.58 (d, J = 10.07 Hz, 1 H), 3.03 (d, J = 11.29 Hz, 2 H),2.78-2.86 (m, 2 H), 2.66 (t, J = 7.48 Hz, 2 H), 2.06 (s, 1 H), 1.87-1.96(m, 1 H), 1.55-1.61 (m, 2 H), 1.51-1.54 (m, 1 H) 61

1.83 393.0 ¹H NMR (400 MHz, DMSO- d₆) δ ppm 9.02 (1 H, br. s.), 8.04 (1H, d, J = 2.01 Hz), 7.49-7.53 (1 H, m), 7.43-7.47 (1 H, m), 3.88 (1 H,d, J = 10.07 Hz), 3.63 (1 H, d, J = 10.07 Hz), 3.02 (2 H, s), 2.74-2.84(2 H, m), 2.65 (2 H, t, J = 7.68 Hz), 2.06 (1 H, d, J = 2.52 Hz), 1.89(1 H, br. s.), 1.42-1.64 (3 H, m) 62

1.16 391.1 ¹H NMR (400 MHz, DMSO- d₆) δ ppm 9.21 (1 H, br. s.), 8.40 (1H, d, J = 1.51 Hz), 7.80- 7.85 (1 H, m), 7.72-7.77 (1 H, m), 3.92 (1 H,d, J = 10.32 Hz), 3.67 (1 H, d, J = 10.07 Hz), 3.21 (3 H, s), 3.05 (2 H,d, J = 4.03 Hz), 2.82 (2 H, d, J = 6.80 Hz), 2.67 (2 H, t, J = 7.43 Hz),2.10 (1 H, br. s.), 1.94 (1 H, d, J = 3.27 Hz), 1.45-1.66 (3 H, m) 63

1.35 329.1 ¹H NMR (500 MHz, DMSO- D6) δ ppm 8.54 (s, 1 H), 7.32 (s, 1H), 3.79 (d, J = 10.07 Hz, 1 H), 3.54 (d, J = 10.07 Hz, 1 H), 2.98-3.05(m, 2 H), 2.76-2.85 (m, 2 H), 2.66 (t, J = 7.63 Hz, 2 H), 2.05 (s, 1 H),1.87-1.95 (m, 1 H), 1.41- 1.68 (m, 3 H) 64

1.02 349.9 ¹H NMR (500 MHz, DMSO- d6) δ ppm 8.54 (s, 1 H), 7.32 (s, 1H), 3.67 (dd, J = 126.04, 10.07 Hz, 2 H), 2.92-3.09 (m, 2 H), 2.72-2.91(m, 2 H), 2.60-2.73 (m, J = 7.63, 7.63 Hz, 2 H), 2.00-2.12 (m, 1 H),1.81-1.99 (m, 1 H), 1.35- 1.69 (m, 3 H) 65

2.14 380   ¹H NMR (500 MHz, DMSO- d₆) δ ppm 8.93 (s, 1 H), 7.54- 7.76(m, J = 10.53, 3.81 Hz, 2 H), 3.79-4.04 (m, 1 H), 3.56- 3.72 (m, J =9.92, 3.20 Hz, 1 H), 3.26-3.45 (m, 2 H), 2.98- 3.12 (m, 2 H), 2.75-2.90(m, 2 H), 2.61-2.74 (m, J = 1.22 Hz, 2 H), 2.09 (s, 1 H), 1.87-2.04 (m,1 H), 1.42- 1.76 (m, 3 H) 66

1.26 333.1 ¹H NMR (500 MHz, DMSO- d₆) δ ppm 9.04 (1 H, d, J = 1.22 Hz),8.44 (1 H, br. s.), 7.52-7.69 (2 H, m), 3.77- 3.82 (1 H, m), 3.68 (1 H,d, J = 10.07 Hz), 3.05-3.12 (2 H, m), 2.94-3.04 (2 H, m), 2.80- 2.91 (2H, m), 2.19 (1 H, d, J = 1.83 Hz), 2.01 (1 H, br. s.), 1.67-1.85 (3 H,m) 67

0.28 277.1 ¹H NMR (500 MHz, DMSO- d₆) δ ppm 6.72-7.61 (m, 1 H),3.49-3.70 (m, 1 H), 3.31- 3.46 (m, 1 H), 2.86-3.06 (m, J = 9.46 Hz, 2H), 2.56- 2.84 (m, 4 H), 2.10-2.31 (m, 3 H), 1.91-2.10 (m, 4 H), 1.70(s, 1 H), 1.49-1.61 (m, 2 H), 1.36-1.49 (m, 1 H) 68

0.44 276.2 ¹H NMR (500 MHz, DMSO- d₆) δ ppm 7.55 (s, 1 H), 5.63 (s, 1H), 3.57-3.74 (m, J = 8.55 Hz, 1 H), 3.48 (s, 3 H), 2.96 (s, 2 H),2.72-2.88 (m, 2 H), 2.65 (s, 2 H), 1.93-2.17 (m, 4 H), 1.86 (s, 1 H),1.57 (s, 3 H) 69

1.35 339.1 ¹H NMR (500 MHz, DMSO- d₆) δ ppm 7.87 (d, J = 6.71 Hz, 1 H),7.80 (d, J = 7.02 Hz, 2 H), 7.42-7.48 (m, 4 H), 3.49- 3.57 (m, 1 H),3.25-3.33 (m, 4 H), 2.77 (t, J = 15.41 Hz, 2 H), 2.59-2.68 (m, 1 H),2.49-2.57 (m, 15 H), 2.24- 2.31 (m, 2 H), 2.21 (s, 1 H), 1.94 (s, 1 H),1.47 (s, 2 H) 70

0.73 340.1 ¹H NMR (300 MHz, DMSO- d₆) δ ppm 9.20 (1 H, br. s.),8.29-8.42 (1 H, m), 7.63- 7.76 (2 H, m), 3.91 (1 H, d, J = 10.25 Hz),3.66 (1 H, d, J = 10.25 Hz), 3.05 (2 H, s), 2.74-2.90 (2 H, m), 2.66 (2H, t, J = 7.68 Hz), 2.09 (1 H, br. s.), 1.92 (1 H, d, J = 4.03 Hz),1.42-1.66 (3 H, m) 71

1.00 315.1 ¹H NMR (400 MHz, CDCl₃) δ ppm 8.92 (1 H, s), 8.00 (1 H, br.s.), 7.78 (1 H, d, J = 8.56 Hz), 7.42 (1 H, d, J = 8.06 Hz), 3.92 (1 H,d, J = 11.08 Hz), 3.55 (1 H, d, J = 10.83 Hz), 3.23 (1 H, d, J = 14.86Hz), 2.83-2.90 (2 H, m), 2.65- 2.83 (2 H, m), 1.89-2.17 (3 H, m),1.41-1.75 (3 H, m) 72

0.75 315.1 ¹H NMR (400 MHz, CDCl₃) δ ppm 8.82 (1 H, s), 8.22 (1 H, s),7.98 (1 H, d, J = 8.56 Hz), 7.21-7.25 (1 H, m), 6.37 (1 H, br. s.), 3.99(1 H, d, J = 11.58 Hz), 3.61 (1 H, d, J = 11.58 Hz), 3.23 (1 H, d, J =14.86 Hz), 2.89 (2 H, t, J = 7.68 Hz), 2.69-2.84 (2 H, m), 1.91-2.09 (2H, m), 1.45- 1.73 (4 H, m) 73

0.85 309.2 ¹H NMR (400 MHz, CDCl₃) δ ppm 8.70 (1 H, d, J = 1.76 Hz),8.09 (1 H, br. s.), 8.00 (1 H, d, J = 8.31 Hz), 7.43-7.58 (2 H, m), 3.90(1 H, d, J = 10.58 Hz), 3.54 (1 H, d, J = 10.32 Hz), 3.26 (1 H, d, J =14.60 Hz), 2.65-3.06 (5 H, m), 2.13 (1 H, br. s.), 2.00 (1 H, br. s.),1.34-1.79 (5 H, m) 74

0.65 313.2 ¹H NMR (500 MHz, MeOD) δ ppm 8.55 (1 H, s), 7.66- 7.70 (1 H,m), 7.59-7.63 (1 H, m), 4.25 (1 H, d, J = 10.99 Hz), 4.04 (1 H, d, J =10.68 Hz), 3.91 (1 H, d, J = 14.95 Hz), 3.76 (1 H, dd, J = 14.95, 2.44Hz), 3.45-3.53 (1 H, m), 3.29-3.40 (3 H, m), 2.61 (1 H, d, J = 2.14 Hz),2.40 (3 H, s), 2.31 (1 H, tt, J = 10.26, 3.47 Hz), 2.06-2.16 (1 H, m, J= 14.23, 9.35, 4.54, 4.54 Hz), 1.92-2.06 (2 H, m) 75

1.24 310.1 ¹H NMR (400 MHz, CDCl₃) δ ppm 8.73 (1 H, d, J = 1.76 Hz),8.66 (1 H, d, J = 2.01 Hz), 7.96 (1 H, d, J = 9.07 Hz), 7.90 (1 H, br.s.), 7.68 (1 H, br. s.), 7.50 (1 H, br. s.), 3.93 (1 H, d, J = 10.32Hz), 3.56 (1 H, d, J = 9.32 Hz), 3.29 (1 H, d, J = 14.86 Hz), 2.97 (1 H,d, J = 14.86 Hz), 2.88-2.94 (2 H, m), 2.69-2.87 (2 H, m), 2.12 (1 H, br.s.), 2.06 (1 H, br. s.), 1.64-1.73 (1 H, m), 1.46- 1.64 (2 H, m) 76

1.58 328.2 ¹H NMR (500 MHz, DMSO- d₆) δ ppm 11.30 (s, 1 H), 9.16 (s, 1H), 7.04-7.43 (m, 1 H), 6.70-7.03 (m, 1 H), 6.54- 6.69 (m, 1 H), 3.89(d, J = 9.77 Hz, 1 H), 3.53-3.81 (m, 4 H), 3.01 (s, 2 H), 2.58-2.91 (m,4 H), 2.03 (s, 1 H), 1.78-1.96 (m, 1 H), 1.32-1.73 (m, 3 H) 77

1.40 316.1 ¹H NMR (500 MHz, DMSO- D6) δ ppm 11.53 (s, 1 H), 9.12 (s, 1H), 6.94-7.46 (m, 2 H), 6.83 (s, 2 H), 3.90 (d, J = 9.77 Hz, 1 H), 3.64(d, J = 9.77 Hz, 1 H), 2.90-3.09 (m, 2 H), 2.61-2.87 (m, 4 H), 1.95-2.10(m, 1 H), 1.88 (d, J = 3.05 Hz, 1 H), 1.33-1.70 (m, 3 H) 78

0.35 298.1 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.94 (1 H, s), 7.80 (1 H, br.s.), 7.26-7.36 (1 H, m), 7.17-7.25 (1 H, m), 3.97 (1 H, d, J = 11.33Hz), 3.59 (1 H, d, J = 11.58 Hz), 3.23 (1 H, d, J = 14.60 Hz), 2.65-3.01(5 H, m), 1.86-2.16 (2 H, m), 1.35- 1.73 (3 H, m) 79

1.10 376.1 ¹H NMR (400 MHz, CDCl₃) δ ppm 8.78 (2 H, d, J = 5.79 Hz),8.03 (2 H, d, J = 6.04 Hz), 7.73 (1 H, br. s.), 7.48 (1 H, d, J = 8.56Hz), 7.36 (1 H, br. s.), 3.92 (1 H, d, J = 8.81 Hz), 3.55 (1 H, d, J =9.06 Hz), 3.24 (1 H, d, J = 14.10 Hz), 2.57-3.06 (5 H, m), 1.86-2.20 (2H, m), 1.30-1.80 (3 H, m) 80

2.36 393.1 ¹H NMR (400 MHz, CDCl₃) δ ppm 8.00 (1 H, d, J = 7.81 Hz),7.83-7.97 (1 H, m), 7.68 (1 H, br. s.), 7.39-7.55 (2 H, m), 7.35 (1 H,br. s.), 7.20 (2 H, td, J = 8.31, 2.27 Hz), 3.93 (1 H, d, J = 10.83 Hz),3.56 (1 H, d, J = 10.58 Hz), 3.24 (1 H, d, J = 15.11 Hz), 2.62-3.05 (5H, m), 1.88-2.22 (2 H, m), 1.34- 1.79 (3 H, m) 81

2.81 403.1 ¹H NMR (400 MHz, CDCl₃) δ ppm 8.12 (2 H, d, J = 8.06 Hz),7.64 (1 H, br. s.), 7.43 (1 H, d, J = 8.56 Hz), 7.32 (3 H, d, J = 8.06Hz), 3.94 (1 H, d, J = 10.07 Hz), 3.56 (1 H, d, J = 9.57 Hz), 3.24 (1 H,d, J = 13.60 Hz), 2.57-3.03 (7 H, m), 1.88-2.22 (2 H, m), 1.39- 1.74 (3H, m), 1.27 (3 H, t, J = 7.68 Hz) 82

2.62 418.1 ¹H NMR (400 MHz, CDCl₃) δ ppm 8.06 (2 H, d, J = 9.07 Hz),7.56 (1 H, br. s.), 7.30-7.43 (2 H, m), 6.74 (2 H, d, J = 9.07 Hz), 3.95(1 H, d, J = 11.58 Hz), 3.58 (1 H, d, J = 11.83 Hz), 3.24 (1 H, d, J =14.10 Hz), 3.05 (6 H, s), 2.61-2.99 (5 H, m), 1.88-2.13 (2 H, m),1.35-1.81 (4 H, m) 83

1.15 367.1 ¹H NMR (500 MHz, MeOD) δ ppm 9.12 (1 H, s), 7.78- 7.82 (1 H,m), 7.70-7.74 (1 H, m), 4.05 (1 H, d, J = 9.77 Hz), 3.75 (1 H, d, J =9.77 Hz), 3.29 (1 H, d, J = 14.65 Hz), 3.11-3.18 (1 H, m), 2.98 (2 H, t,J = 7.93 Hz), 2.80-2.91 (2 H, m), 2.13-2.22 (2 H, m), 1.71-1.87 (2 H,m), 1.62- 1.71 (1 H, m) 84

1.96 393.1 ¹H NMR (400 MHz, CDCl₃) δ ppm 8.18-8.26 (2 H, m), 7.66 (1 H,s), 7.44 (1 H, d, J = 8.56 Hz), 7.32 (1 H, d, J = 8.56 Hz), 7.16-7.23 (2H, m), 3.95 (1 H, d, J = 11.33 Hz), 3.57 (1 H, d, J = 11.33 Hz), 3.25 (1H, d, J = 14.60 Hz), 2.69-3.04 (6 H, m), 2.09 (1 H, br. s.), 1.45- 1.74(4 H, m) 85

1.34 309.1 ¹H NMR (400 MHz, CDCl₃) δ ppm 8.75 (1 H, dd, J = 4.15, 1.64Hz), 8.04 (1 H, d, J = 8.06 Hz), 7.98 (2 H, d, J = 8.81 Hz), 7.49 (1 H,d, J = 8.81 Hz), 7.31 (1 H, dd, J = 8.31, 4.28 Hz), 6.71 (1 H, br. s.),4.03 (1 H, d, J = 11.83 Hz), 3.65 (1 H, d, J = 12.09 Hz), 3.25 (1 H, d,J = 14.86 Hz), 2.96 (1 H, d, J = 14.86 Hz), 2.89 (2 H, t, J = 7.55 Hz),2.69-2.84 (2 H, m), 2.07 (1 H, br. s.), 1.98 (1 H, br. s.), 1.57-1.73 (2H, m), 1.44-1.55 (1 H, m) 86

1.16 313.1 ¹H NMR (400 MHz, CDCl₃) δ ppm 9.78 (1 H, br. s.), 7.19 (1 H,br. s.), 6.99 (1 H, d, J = 6.80 Hz), 6.67 (1 H, d, J = 8.31 Hz), 3.87 (1H, d, J = 10.32 Hz), 3.50 (1 H, d, J = 11.08 Hz), 3.46 (2 H, s), 3.21 (1H, d, J = 14.60 Hz), 2.93 (1 H, d, J = 15.11 Hz), 2.87 (2 H, t, J = 7.68Hz), 2.65- 2.81 (2 H, m), 2.04 (1 H, br. s.), 1.96 (1 H, br. s.), 1.40-1.75 (3 H, m) 87

1.13 299.2 ¹H NMR (500 MHz, MeOD) δ ppm 8.57-8.63 (1 H, m), 7.55-7.64 (2H, m), 7.06- 7.12 (1 H, m), 4.04 (1 H, dd, J = 9.92, 1.98 Hz), 3.81 (1H, dd, J = 10.07, 2.14 Hz), 3.46- 3.57 (1 H, m), 3.23 (2 H, d, J = 10.68Hz), 3.09-3.18 (2 H, m), 2.82-3.02 (1 H, m), 2.41 (1 H, br. s.),2.28-2.37 (1 H, m), 1.99-2.07 (1 H, m), 1.86- 1.97 (2 H, m) 88

1.26 342.1 ¹H NMR (500 MHz, DMSO- d₆) δ ppm 9.20 (s, 1 H), 8.64 (s, 1H), 8.45-8.56 (m, J = 4.58, 1.53 Hz, 1 H), 8.21- 8.38 (m, J = 7.63 Hz, 1H), 7.62 (s, 1 H), 7.33-7.50 (m, J = 7.93, 4.88 Hz, 1 H), 3.75 (dd, J =128.64, 9.92 Hz, 2 H), 2.95-3.14 (m, 2 H), 2.62- 2.91 (m, 4 H), 2.06 (s,1 H), 1.92 (s, 1 H), 1.42-1.70 (m, 3 H) 89

2.13 343.1 ¹H NMR (500 MHz, DMSO- d₆) δ ppm 8.81 (s, 1 H), 7.39 (s, 1H), 6.97 (s, 1 H), 3.78 (dd, J = 130.16, 9.92 Hz, 2 H), 2.95-3.15 (m, 2H), 2.74- 2.90 (m, 2 H), 2.61-2.72 (m, J = 7.78, 7.78 Hz, 2 H), 2.47-2.55 (m, J = 3.66, 1.83 Hz, 3 H), 2.33 (s, 3 H), 2.07 (s, 1 H),1.85-2.01 (m, 1 H), 1.41- 1.70 (m, 3 H) 90

0.55 372.0 ¹H NMR (300 MHz, DMSO- d₆) δ ppm 9.98 (1 H, s), 8.92 (1 H,br. s.), 8.11 (1 H, d, J = 1.83 Hz), 7.48-7.53 (1 H, m), 7.34-7.40 (1 H,m), 3.88 (1 H, d, J = 10.25 Hz), 3.62 (1 H, d, J = 10.25 Hz), 3.02 (2 H,s), 2.74-2.83 (2 H, m), 2.66 (2 H, t, J = 7.50 Hz), 2.04 (4 H, s), 1.90(1 H, br. s.), 1.58 (3 H, br. s.) 91

1.60 343.3 ¹H NMR (300 MHz, DMSO- d₆) δ ppm 7.61 (1 H, s), 7.47- 7.53 (1H, m), 7.16 (1 H, d, J = 8.05 Hz), 3.84-3.92 (1 H, m), 3.62 (1 H, d, J =10.25 Hz), 3.26-3.46 (3 H, m), 3.02 (1 H, s), 2.79 (1 H, d, J = 6.95Hz), 2.65 (2 H, q, J = 7.32 Hz), 2.01-2.20 (1 H, m), 1.93 (2 H, d, J =9.88 Hz), 1.40-1.64 (2 H, m), 1.15-1.28 (3 H, m), 1.00 (1 H, d, J = 6.59Hz) 92

0.45 279.1 ¹H NMR (500 MHz, DMSO- D6) δ ppm 8.34-8.83 (m, 1 H), 6.96 (s,1 H), 3.79 (d, J = 9.77 Hz, 2 H), 3.53 (d, J = 9.77 Hz, 2 H), 2.89-3.06(m, 2 H), 2.71-2.86 (m, 2 H), 2.60-2.70 (m, J = 7.78, 7.78 Hz, 2 H),2.29 (s, 3 H), 2.01 (s, 1 H), 1.90 (d, J = 13.43 Hz, 2 H), 1.35-1.65 (m,3 H) 93

1.79 355.1 ¹H NMR (500 MHz, DMSO- d₆) δ ppm 8.74 (s, 1 H), 7.62- 7.88(m, 1 H), 3.83 (d, J = 10.07 Hz, 1 H), 3.63-3.76 (m, 2 H), 3.58 (d, J =10.07 Hz, 1 H), 3.40-3.53 (m, 2 H), 2.96-3.10 (m, 2 H), 2.73- 2.90 (m, 2H), 2.58-2.72 (m, J = 7.63, 7.63 Hz, 2 H), 2.06 (s, 1 H), 1.75-1.99 (m,5 H), 1.43-1.69 (m, 3 H) 94

1.53 313.1 ¹H NMR (500 MHz, MeOD) δ ppm 8.63 (1 H, d, J = 7.02 Hz), 7.55(1 H, s), 7.19-7.23 (1 H, m), 4.27 (1 H, d, J = 10.68 Hz), 4.06 (1 H, d,J = 10.68 Hz), 3.94 (1 H, d, J = 14.95 Hz), 3.76-3.83 (1 H, m), 3.54 (1H, t, J = 11.90 Hz), 3.36-3.48 (3 H, m), 2.64 (1 H, d, J = 1.83 Hz),2.56 (3 H, s), 2.34-2.42 (1 H, m, J = 10.15, 10.15, 3.66, 3.51 Hz), 2.17(1 H, dddd, J = 14.19, 9.46, 4.58, 4.43 Hz), 1.97-2.11 (2 H, m) 95

0.63 260.2 ¹H NMR (400 MHz, CDCl₃) δ ppm 9.05 (1 H, br. s.), 8.34 (1 H,s), 8.04 (1 H, dd, J = 2.77, 1.26 Hz), 8.00 (1 H, d, J = 2.77 Hz), 3.91(1 H, d, J = 9.32 Hz), 3.57 (1 H, d, J = 9.57 Hz), 3.31 (1 H, dd, J =14.98, 1.64 Hz), 2.65-3.02 (5 H, m), 2.10-2.20 (1 H, m), 2.05-2.09 (1 H,m), 1.63- 1.75 (1 H, m), 1.40-1.60 (2 H, m) 96

1.88 338.1 ¹H NMR (500 MHz, DMSO- D6) δ ppm 8.85 (s, 1 H), 7.41- 7.47(m, 4 H), 7.28-7.35 (m, 1 H), 6.85 (s, 1 H), 3.83 (d, J = 9.77 Hz, 1 H),3.57 (d, J = 9.77 Hz, 1 H), 3.46-3.51 (m, 3 H), 3.00 (s, 2 H), 2.78 (t,J = 7.78 Hz, 2 H), 2.67 (t, J = 7.78 Hz, 2 H), 1.98-2.03 (m, 1 H),1.85-1.93 (m, 1 H), 1.54-1.63 (m, J = 8.16, 7.82, 7.82, 3.05 Hz, 2 H),1.43- 1.51 (m, 1 H) 97

1.57 313.1 ¹H NMR (500 MHz, MeOD) δ ppm 8.61 (1 H, d, J = 6.71 Hz), 7.65(1 H, d, J = 7.32 Hz), 7.25 (1 H, t, J = 7.02 Hz), 4.32 (1 H, d, J =10.99 Hz), 4.11 (1 H, d, J = 10.68 Hz), 3.98 (1 H, dd, J = 14.80, 1.68Hz), 3.82 (1 H, dd, J = 14.95, 2.14 Hz), 3.52- 3.61 (1 H, m), 3.35-3.47(3 H, m), 2.66-2.71 (1 H, m), 2.62 (3 H, s), 2.34-2.44 (1 H, m),2.14-2.24 (1 H, m), 1.99- 2.13 (2 H, m) 98

0.57 350.1 ¹H NMR (500 MHz, DMSO- D6) δ ppm 8.64 (s, 1 H), 3.82 (d, J =10.07 Hz, 1 H), 3.57 (d, J = 9.77 Hz, 1 H), 3.02 (s, 2 H), 2.97 (s, 6H), 2.79 (s, 2 H), 2.67 (t, J = 7.63 Hz, 2 H), 2.19 (s, 3 H), 2.04 (s, 1H), 1.85- 1.94 (m, 1 H), 1.58 (s, 2 H), 1.49 (d, J = 6.71 Hz, 1 H) 99

0.87 290.1 ¹H NMR (400 MHz, MeOD) δ ppm 8.20 (1 H, d, J = 5.79 Hz), 6.34(1 H, d, J = 5.79 Hz), 3.94-4.04 (1 H, m), 3.91 (3 H, s), 3.55-3.76 (1H, m), 3.00-3.28 (2 H, m), 2.63- 2.97 (4 H, m), 1.99-2.21 (2 H, m),1.44-1.85 (3 H, m) 100 

0.91 290.1 ¹H NMR (400 MHz, MeOD) δ ppm 8.39 (1 H, s), 6.21 (1 H, d, J =6.04 Hz), 3.98 (1 H, d, J = 10.32 Hz), 3.89 (3 H, s), 3.67 (1 H, d, J =10.32 Hz), 3.01-3.24 (2 H, m), 2.65- 2.97 (4 H, m), 1.96-2.17 (2 H, m),1.43-1.81 (3 H, m) 101 

1.18 260.1 ¹H NMR (400 MHz, MeOD) δ ppm 8.56 (2 H, d, J = 4.78 Hz),6.94-6.99 (1 H, m), 3.98- 4.04 (1 H, m), 3.78 (1 H, d, J = 10.32 Hz),3.45-3.52 (1 H, m), 3.35 (1 H, s), 3.15-3.22 (2 H, m), 3.05-3.12 (2 H,m), 2.22-2.38 (2 H, m), 1.95- 2.03 (1 H, m), 1.80-1.92 (2 H, m) 102 

2.19 343.4 ¹H NMR (500 MHz, DMSO- d₆) δ ppm 8.87 (1 H, br. s.), 7.06 (1H, d, J = 7.63 Hz), 6.91 (1 H, d, J = 7.63 Hz), 3.92 (1 H, d, J = 10.07Hz), 3.66 (1 H, d, J = 10.07 Hz), 3.03 (2 H, s), 2.72-2.85 (2 H, m),2.64- 2.70 (2 H, m), 2.51 (3 H, s), 2.35 (3 H, s), 2.07 (1 H, br. s.),1.91 (1 H, br. s.), 1.55- 1.65 (2 H, m), 1.44-1.53 (1 H, m) 103 

2.48 363.3 ¹H NMR (500 MHz, DMSO- d₆) δ ppm 8.84 (1 H, br. s.), 7.71 (1H, d, J = 1.83 Hz), 7.18 (1 H, s), 3.90 (1 H, d, J = 10.07 Hz), 3.64 (1H, d, J = 10.07 Hz), 3.03 (2 H, s), 2.72-2.85 (2 H, m), 2.66 (2 H, t, J= 7.63 Hz), 2.53 (3 H, s), 2.07 (1 H, br. s.), 1.88-1.96 (1 H, m),1.55-1.63 (2 H, m), 1.44- 1.53 (1 H, m) 104 

1.45 381.0 ¹H NMR (500 MHz, DMSO- d₆) δ ppm 8.99 (1 H, br. s.), 7.69 (1H, d, J = 2.44 Hz), 7.61 (1 H, d, J = 8.55 Hz), 7.01- 7.34 (2 H, m),3.89 (1 H, d, J = 10.07 Hz), 3.64 (1 H, d, J = 10.07 Hz), 3.03 (2 H, d,J = 2.44 Hz), 2.72-2.86 (2 H, m), 2.66 (2 H, t, J = 7.78 Hz), 2.07 (1 H,br. s.), 1.88-1.96 (1 H, m), 1.55-1.64 (2 H, m), 1.45-1.53 (1 H, m) 105 

1.83 355.1 ¹H NMR (500 MHz, DMSO- D6) δ ppm 8.57 (s, 1 H), 7.31 (t, J =7.32 Hz, 2 H), 7.20- 7.26 (m, 3 H), 7.08 (s, 1 H), 4.01 (s, 2 H), 3.78(d, J = 9.77 Hz, 1 H), 3.53 (d, J = 10.07 Hz, 1 H), 2.97 (s, 2 H),2.70-2.78 (m, 2 H), 2.64 (t, J = 7.78 Hz, 2 H), 1.99 (s, 1 H), 1.81-1.90(m, 1 H), 1.52-1.60 (m, 2 H), 1.41-1.49 (m, J = 6.90, 2.90, 2.67, 2.48Hz, 1 H) 106 

0.71 274.2 ¹H NMR (400 MHz, CDCl₃) δ ppm 8.87 (1 H, br. s.), 8.23 (1 H,s), 7.88 (1 H, s), 3.85 (1 H, d, J = 9.32 Hz), 3.51 (1 H, d, J = 9.32Hz), 3.27 (1 H, dd, J = 14.98, 1.64 Hz), 2.60-2.97 (5 H, m), 2.37 (3 H,s), 2.06- 2.16 (1 H, m, J = 13.25, 9.85, 3.46, 3.46, 3.46 Hz), 1.99-2.05 (1 H, m), 1.57-1.70 (1 H, m), 1.36-1.54 (2 H, m) 107 

0.93 338.1 ¹H NMR (400 MHz, CDCl₃) δ ppm 8.71 (1 H, br. s.), 8.14 (1 H,d, J = 1.26 Hz), 8.11 (1 H, d, J = 1.26 Hz), 3.92 (1 H, d, J = 9.32 Hz),3.58 (1 H, d, J = 9.57 Hz), 3.32 (1 H, dd, J = 14.98, 1.89 Hz),2.68-3.03 (5 H, m), 2.04-2.19 (2 H, m), 1.63-1.75 (1 H, m, J = 14.01,9.85, 4.31, 4.31 Hz), 1.42- 1.59 (2 H, m) 108 

2.34 375.0 ¹H NMR (500 MHz, DMSO- D6) δ ppm 8.58 (s, 1 H), 7.98 (d, J =8.24 Hz, 2 H), 7.51 (s, 1 H), 7.45 (d, J = 8.54 Hz, 2 H), 3.87 (d, J =10.07 Hz, 1 H), 3.62 (d, J = 9.77 Hz, 1 H), 3.04 (s, 2 H), 2.75-2.87 (m,2 H), 2.68 (t, J = 7.63 Hz, 2 H), 2.07 (s, 1 H), 1.92 (s, 1 H), 1.40-1.68 (m, 3 H) 109 

0.73 279.3 ¹H NMR (400 MHz, DMSO- D6) δ ppm 8.61 (s, 1 H), 6.54 (d, J =1.01 Hz, 1 H), 3.80 (d, J = 10.07 Hz, 1 H), 3.54 (d, J = 9.82 Hz, 1 H),2.98 (s, 2 H), 2.70-2.81 (m, 2 H), 2.65 (t, J = 7.81 Hz, 2 H), 2.20 (s,3 H), 1.95-2.05 (m, 1 H), 1.88 (s, 1 H), 1.50-1.61 (m, 2 H), 1.41- 1.50(m, 1 H) 110 

1.76 321.4 ¹H NMR (400 MHz, DMSO- D6) δ ppm 8.24-8.82 (m, 1 H), 6.51 (s,1 H), 3.83 (d, J = 9.57 Hz, 1 H), 3.57 (d, J = 9.32 Hz, 1 H), 2.98 (s, 2H), 2.70-2.82 (m, 2 H), 2.65 (t, J = 7.68 Hz, 2 H), 1.97-2.04 (m, 1 H),1.88 (s, 1 H), 1.52- 1.61 (m, 2 H), 1.46 (dd, J = 9.69, 2.90 Hz, 1 H),1.24 (s, 9 H) 111 

1.64 312.3 ¹H NMR (400 MHz, DMSO- d₆) δ ppm 8.55 (s, 1 H), 7.13 (d, J =8.56 Hz, 2 H), 7.04 (s, 1 H), 6.86 (d, J = 8.56 Hz, 2 H), 3.92 (s, 2 H),3.66-3.85 (m, 4 H), 3.45-3.60 (m, J = 10.07 Hz, 1 H), 2.95 (s, 2 H),2.57- 2.86 (m, 4 H), 1.98 (s, 1 H), 1.84 (s, 1 H), 1.31-1.66 (m, 2 H)112 

1.70 359.1 ¹H NMR (300 MHz, DMSO- d₆) δ ppm 8.83 (1 H, d, J = 1.83 Hz),7.08 (1 H, d, J = 8.42 Hz), 6.71 (1 H, d, J = 8.05 Hz), 3.87- 3.94 (1 H,m), 3.85 (3 H, s), 3.65 (1 H, d, J = 9.88 Hz), 3.04 (2 H, s), 2.61-2.85(4 H, m), 2.47 (3 H, s), 2.08 (1 H, d, J = 2.20 Hz), 1.82-1.99 (1 H, m),1.41-1.66 (3 H, m) 113 

1.48 298.3 ¹H NMR (500 MHz, DMSO- d₆) δ ppm 12.09 (s, 1 H), 8.02 (s, 1H), 7.63 (d, J = 7.32 Hz, 1 H), 7.33-7.36 (m, 1 H), 7.30 (d, J = 5.80Hz, 1 H), 6.99 (t, J = 7.02 Hz, 1 H), 3.82 (d, J = 8.24 Hz, 1 H), 3.57(s, 1 H), 3.00 (s, 2 H), 2.79 (s, 2 H), 2.67 (s, 2 H), 1.99-2.04 (m, 1H), 1.93 (s, 1 H), 1.58 (s, 2 H), 1.47 (s, 1 H)

The compounds in Table 3 were synthesized according to the method ofExample 21, steps C-D using the appropriate isothiocyanate or amine andracemic 3-(aminomethyl)quinuclidin-3-ol, 2HCl.

TABLE 3

Example LCMS RT LCMS Ion Number R₁ (min) [M + H]⁺ ¹H NMR 114

2.06 344.3 ¹H NMR (400 MHz, DMSO- d₆) δ ppm 9.02 (1 H, s), 7.10 (1 H,s), 3.67-3.88 (2 H, m), 3.07-3.30 (2 H, m), 2.80- 3.05 (4 H, m), 2.78 (3H, s), 2.55 (3 H, s), 2.22 (1 H, br. s.), 2.00 (1 H, d, J = 12.09 Hz),1.55-1.88 (3 H, m) 115

1.19 260.3 ¹H NMR (400 MHz, MeOD) δ ppm 8.70 (1 H, dd, J = 4.41, 1.39Hz), 7.51 (1 H, dd, J = 8.81, 4.53 Hz), 7.15 (1 H, d, J = 7.81 Hz), 4.03(1 H, d, J = 10.07 Hz), 3.72 (1 H, d, J = 10.07 Hz), 3.14-3.26 (1 H, m),3.03-3.14 (1 H, m), 2.85- 2.99 (2 H, m), 2.69-2.84 (2 H, m), 2.00-2.26(2 H, m), 1.51-1.87 (3 H, m) 116

0.73 290.3 ¹H NMR (400 MHz, MeOD) δ ppm 6.99-7.12 (2 H, m), 3.95-4.02 (4H, m), 3.68 (1 H, d, J = 10.07 Hz), 3.20 (1 H, dd), 3.08 (1 H, dd),2.84- 2.95 (2 H, m), 2.69-2.84 (2 H, m), 1.99-2.21 (2 H, m), 1.47-1.87(3 H, m) 117

¹H NMR (400 MHz, MeOD) δ ppm 8.71 (1 H, s), 8.33 (1 H, d, J = 5.54 Hz),6.84 (1 H, br.s.), 4.04 (1 H, d, J = 10.32 Hz), 3.73 (1 H, d, J = 10.32Hz), 3.17-3.25 (1 H, m), 3.04- 3.13 (1 H, m), 2.70-3.00 (4 H, m),2.02-2.18 (2 H, m), 1.51-1.81 (3 H, m) 118

0.83 290.3 ¹H NMR (400 MHz, CDCl₃) δ ppm 8.48 (1 H, br.s.), 7.96 (1 H,br.s.), 7.71 (1 H, s), 3.91 (1 H, d, J = 9.32 Hz), 3.87 (3 H, s), 3.57(1 H, d, J = 9.32 Hz), 3.30 (1 H, d, J = 14.86 Hz), 2.62-3.03 (5 H, m),2.09- 2.21 (1 H, m), 2.08 (1 H, br. s.), 1.61-1.78 (1 H, m), 1.39- 1.60(2 H, m) 119

0.84 290.3 ¹H NMR (400 MHz, CDCl₃) δ ppm 8.56 (1 H, br.s.), 7.96 (1 H,d, J = 1.26 Hz), 7.79 (1 H, d, J = 1.51 Hz), 3.89 (3 H, s), 3.85 (1 H,s), 3.53 (1 H, d, J = 9.06 Hz), 3.31 (1 H, d, J = 14.86 Hz), 2.65-3.04(5 H, m), 2.11-2.23 (1 H, m, J = 9.85, 9.85, 6.74, 3.53 Hz), 2.08 (1 H,br.s.), 1.62-1.75 (1 H, m), 1.40-1.61 (2 H, m) 120

0.75 290.3 ¹H NMR (400 MHz, CDCl₃) δ ppm 9.30 (1 H, br.s.), 7.58 (1 H,d, J = 3.02 Hz), 7.52 (1 H, d, J = 3.02 Hz), 3.92 (3 H, s), 3.88 (1 H,d, J = 9.32 Hz), 3.54 (1 H, d, J = 9.32 Hz), 3.28 (1 H, dd, J = 14.86,1.51 Hz), 2.63-2.96 (5 H, m), 2.07- 2.22 (1 H, m), 2.02 (1 H, br. s.),1.57-1.71 (1 H, m), 1.33- 1.55 (2 H, m) 121

1.15 316.4 ¹H NMR (400 MHz, MeOD) δ ppm 8.65 (1 H, d, J = 3.02 Hz), 6.82(1 H, br.s.), 4.02 (1 H, dd, J = 10.32, 3.02 Hz), 3.71 (1 H, dd, J =10.32, 3.02 Hz), 2.98-3.26 (2 H, m), 2.66- 2.96 (4 H, m), 1.97-2.18 (2H, m), 1.48-1.86 (3 H, m), 1.29 (9 H, s) 122

1.73 309.3 ¹H NMR (400 MHz, MeOD) δ ppm 8.99 (1 H, s), 7.90 (1 H, d, J =8.31 Hz), 7.70 (1 H, d, J = 8.31 Hz), 7.57 (1 H, t, J = 7.55 Hz), 7.39(1 H, t, J = 7.55 Hz), 7.30 (1 H, br.s.), 3.94 (1 H, d, J = 9.82 Hz),3.63 (1 H, d, J = 10.07 Hz), 3.14- 3.24 (1 H, m), 3.00-3.10 (1 H, m),2.68-2.98 (4 H, m), 2.01-2.24 (2 H, m), 1.45- 1.87 (3 H, m) 123

0.79 288.30 ¹H NMR (400 MHz, MeOD- d₄) δ ppm 6.51 (1 H, br.s.), 4.03 (1H, d, J = 10.32 Hz), 3.71 (1 H, d, J = 10.32 Hz), 3.12-3.24 (1 H, m),3.01- 3.12 (1 H, m), 2.72-3.00 (4 H, m), 2.52 (3 H, s), 2.33 (3 H, s),1.98-2.20 (2 H, m), 1.51-1.87 (3 H, m) 124

0.72 274.30 ¹H NMR (400 MHz, MeOD- d₄) δ ppm 7.42 (1 H, d, J = 9.07 Hz),7.07 (1 H, d, J = 8.06 Hz), 4.02 (1 H, d, J = 10.07 Hz), 3.71 (1 H, d, J= 10.07 Hz), 3.15-3.25 (1 H, m), 3.04- 3.14 (1 H, m), 2.69-2.98 (4 H,m), 2.55 (3 H, s), 1.99- 2.21 (2 H, m), 1.47-1.89 (3 H, m)

The compounds in Table 3 were synthesized according to the method ofExample 21, steps C-D using the appropriate isothiocyanate or amine and(S)-3-(aminomethyl)quinuclidin-3-ol, 2HCl.

TABLE 3

LCMS Example LCMS Ion Number R₁ RT (min) [M + H]⁺ ¹H NMR 125

2.06 329.11 ¹H NMR (500 MHz, MeOD- d₄) δ ppm 8.37 (d, J = 7.32 Hz, 1 H),6.92 (d, J = 2.75 Hz, 1 H), 6.65-6.75 (m, 1 H), 4.01 (d, J = 9.77 Hz, 1H), 3.86-3.95 (m, 3 H), 3.70 (d, J = 9 .77 Hz, 1 H), 3.26 (d, J = 14.95Hz, 2 H), 3.12 (d, J = 14.95 Hz, 1 H), 2.96 (t, J = 7.32 Hz, 2 H), 2.76-2.89 (m, 2 H), 2.06-2.26 (m, 2 H), 1.58-1.86 (m, 3 H) 126

0.56 260.30 ¹H NMR (400 MHz, CDCl₃) δ ppm 8.52 (2 H, d, J = 4.78 Hz),6.83 (1 H, t, J = 4.78 Hz), 3.94- 4.10 (2 H, m), 3.87 (1 H, d, J = 14.60Hz), 3.62 (1 H, dd, J = 14.48, 1.89 Hz), 3.41-3.56 (1 H, m), 3.29 (2 H,t, J = 8.44 Hz), 3.04-3.18 (1 H, m), 2.27- 2.50 (2 H, m), 1.88-2.06 (2H, m), 1.71-1.87 (1 H, m) 127

0.88 294.20 ¹H NMR (400 MHz, CDCl₃) δ ppm 8.58 (1 H, br.s.), 8.18 (1 H,s), 7.97 (1 H, s), 3.93 (1 H, d, J = 9.32 Hz), 3.58 (1 H, d, J = 9.57Hz), 3.28 (1 H, dd, J = 14.86, 1.51 Hz), 2.64-2.98 (5 H, m), 2.02-2.15(2 H, m), 1.60-1.73 (1 H, m), 1.38- 1.56 (2 H, m) 128

0.86 294.20 ¹H NMR (400 MHz, CDCl₃) δ ppm 8.72 (1 H, br.s.), 8.12 (1 H,d, J = 0.76 Hz), 8.06 (1 H, d, J = 1.26 Hz), 3.93 (1 H, d, J = 9.32 Hz),3.59 (1 H, d, J = 9.32 Hz), 3.32 (1 H, dd, J = 14.98, 1.38 Hz),2.68-3.02 (5 H, m), 2.05-2.21 (2 H, m), 1.64-1.76 (1 H, m), 1.42- 1.59(2 H, m). M.P.. 185-8° C. 129

2.04 385.28 ¹H NMR (500 MHz, DMSO- D₆) δ ppm 8.48 (s, 1 H), 7.58 (d, J =8.24 Hz, 2 H), 6.98 (d, J = 8.55 Hz, 2 H), 3.73-3.87 (m, 4 H), 3.56 (d,J = 9.16 Hz, 1 H), 3.00 (s, 2 H), 2.72-2.87 (m, 2 H), 2.61-2.72 (m, J =7.63, 7.63 Hz, 2 H), 2.38 (s, 3 H), 2.03 (s, 1 H), 1.91 (s, 1 H),1.37-1.70 (m, 3 H) 130

1.10 368.20 ¹H NMR (400 MHz, CDCl₃) δ ppm 8.97 (1 H, br.s.), 7.67 (1 H,s), 3.94 (3 H, s), 3.89 (1 H, d, J = 9.57 Hz), 3.55 (1 H, d, J = 9.57Hz), 3.28 (1 H, dd, J = 14.86, 1.76 Hz), 2.63-2.95 (5 H, m), 2.08-2.19(1 H, m), 1.99-2.06 (1 H, m), 1.60- 1.70 (1 H, m, J = 14.01, 9.85, 4.31,4.31 Hz), 1.35-1.55 (2 H, m) 131

1.19 336.30 ¹H NMR (400 MHz, CDCl₃) δ ppm 9.06 (1 H, br.s.), 8.52 (1 H,d, J = 1.51 Hz), 8.44 (1 H, d, J = 1.26 Hz), 7.89-7.93 (2 H, m),7.40-7.47 (2 H, m), 7.33- 7.39 (1 H, m), 3.94 (1 H, d, J = 9.32 Hz),3.60 (1 H, d, J = 9.32 Hz), 3.34 (1 H, dd, J = 14.86, 1.76 Hz),2.69-3.05 (5 H, m), 2.13-2.23 (1 H, m), 2.07-2.12 (1 H, m), 1.65- 1.76(1 H, m), 1.44-1.60 (2 H, m) 132

1.35 332.23 ¹H NMR (500 MHz, DMSO- D6) δ ppm 12.40 (s, 1 H), 7.95 (s, 1H), 7.30 (d, J = 8.24 Hz, 1 H), 7.22 (t, J = 7.78 Hz, 2 H), 6.97 (d, J =7.02 Hz, 1 H), 3.79 (d, J = 6.71 Hz, 1 H), 3.53 (s, 1 H), 3.18 (d, J =4.58 Hz, 3 H), 3.00 (s, 2 H), 2.79 (d, J = 2.14 Hz, 2 H), 2.74 (s, 1 H),2.66 (d, J = 7.93 Hz, 3 H), 1.96- 2.04 (m, 2 H), 1.91 (s, 1 H), 1.59 (s,3 H), 1.46 (s, 1 H) 133

1.94 378.16 ¹H NMR (500 MHz, DMSO- D6) δ ppm 12.22 (s, 1 H), 8.32 (s, 1H), 8.01 (s, 1 H), 7.58 (d, J = 8.24 Hz, 1 H), 7.55 (s, 1 H), 7.08-7.14(m, 1 H), 3.82 (d, J = 9.77 Hz, 1 H), 3.56 (d, J = 9.16 Hz, 1 H),2.96-3.04 (m, 2 H), 2.73-2.82 (m, 2 H), 2.67 (t, J = 7.48 Hz, 2 H),2.00- 2.05 (m, 1 H), 1.91 (s, 1 H), 1.54-1.63 (m, 2 H), 1.45 (s, 1 H)134

1.86 332.16 ¹H NMR (500 MHz, DMSO- D6) δ ppm 12.22 (s, 1 H), 8.00 (s, 1H), 7.63 (d, J = 8.55 Hz, 1 H), 7.40 (s, 1 H), 7.00 (d, J = 7.93 Hz, 1H), 3.82 (d, J = 9.46 Hz, 1 H), 3.56 (d, J = 9.16 Hz, 1 H), 3.00 (s, 2H), 2.78 (s, 2 H), 2.67 (t, J = 7.32 Hz, 2 H), 2.02 (s, 1 H), 1.91 (s, 1H), 1.58 (s, 2 H), 1.45 (s, 1 H) 135

1.51 328.28 ¹H NMR (500 MHz, DMSO- D6) δ ppm 11.88 (s, 2 H), 8.01 (s, 1H), 7.48 (d, J = 8.55 Hz, 2 H), 6.73 (s, 2 H), 6.62 (dd, J = 8.70, 1.68Hz, 2 H), 3.77- 3.83 (m, 7 H), 3.55 (d, J = 8.85 Hz, 2 H), 2.97-3.05 (m,4 H), 2.80 (s, 3 H), 2.65-2.72 (m, 4 H), 1.98-2.04 (m, 3 H), 1.92 (s, 2H), 1.60 (d, J = 2.14 Hz, 2 H), 1.59 (s, 2 H), 1.47 (s, 2 H) 136

0.91 338.20 ¹H NMR (400 MHz, CDCl₃) δ ppm 8.69 (1 H, br.s.), 8.12 (1 H,d, J = 1.51 Hz), 8.08 (1 H, d, J = 1.26 Hz), 3.91 (1 H, d, J = 9.57 Hz),3.57 (1 H, d, J = 9.32 Hz), 3.29 (1 H, dd, J = 14.86, 1.51 Hz),2.62-3.01 (5 H, m), 2.01-2.18 (2 H, m), 1.61-1.76 (1 H, m), 1.39- 1.59(2 H, m) 137

0.77 274.30 ¹H NMR (400 MHz, CDCl₃) δ ppm 8.92 (1 H, br.s.), 8.27 (1 H,s), 7.92 (1 H, s), 3.90 (1 H, d, J = 9.32 Hz), 3.56 (1 H, d, J = 9.32Hz), 3.32 (1 H, dd, J = 14.86, 1.76 Hz), 2.67-3.02 (5 H, m), 2.42 (3 H,s), 2.10- 2.21 (1 H, m, J = 13.17, 9.84, 3.49, 3.49, 3.49 Hz), 2.04-2.10 (1 H, m), 1.64-1.74 (1 H, m), 1.39-1.59 (2 H, m) 138

0.84 337.40 ¹H NMR (400 MHz, MeOD- d₄) d ppm 9.39 (1 H, s), 8.57- 8.73(2 H, m), 8.52 (1 H, d, J = 5.79 Hz), 7.56 (1 H, dd, J = 8.06, 5.04 Hz),6.54-7.00 (1 H, m), 4.11 (1 H, d, J = 10.32 Hz), 3.79 (1 H, d, J = 10.58Hz), 3.02-3.29 (2 H, m), 2.72- 3.02 (4 H, m), 2.01-2.25 (2 H, m),1.47-1.89 (3 H, m) 139

1.15 309.30 ¹H NMR (500 MHz, MeOD- d₄) δ ppm 8.07 (1 H, d, J = 8.85 Hz),7.88 (1 H, d, J = 8.24 Hz), 7.75 (1 H, d, J = 7.93 Hz), 7.56- 7.66 (1 H,m), 7.39 (1 H, t, J = 7.48 Hz), 7.06 (1 H, d, J = 8.85 Hz), 4.09 (1 H,d, J = 10.07 Hz), 3.78 (1 H, d, J = 10.07 Hz), 3.27 (1 H, d, J = 14.95Hz), 3.06-3.18 (1 H, m), 2.93-3.01 (2 H, m), 2.75- 2.93 (2 H, m),2.07-2.29 (2 H, m), 1.57-1.88(3 H, m) 140

1.26 327.30 ¹H NMR (500 MHz, MeOD- d₄) δ ppm 8.05 (1 H, d, J = 8.85 Hz),7.92 (1 H, dd, J = 9.00, 5.34 Hz), 7.35-7.49 (2 H, m), 7.08 (1 H, d, J =8.24 Hz), 4.09 (1 H, d, J = 10.07 Hz), 3.78 (1 H, d, J = 10.07 Hz),3.22-3.30 (1 H, m), 3.09-3.18 (1 H, m), 2.91-3.04 (2 H, m), 2.71- 2.91(2 H, m), 2.06-2.30 (2 H, m), 1.56-1.90 (3 H, m) 141

0.80 339.40 ¹H NMR (400 MHz, MeOD- d₄) δ ppm 8.58 (2 H, s), 3.99 (1 H,d, J = 10.07 Hz), 3.69 (1 H, d, J = 10.07 Hz), 3.16-3.24 (1 H, m),3.03-3.12 (1 H, m), 2.85-2.95 (2 H, m), 2.70- 2.85 (2 H, m), 1.96-2.21(2 H, m), 1.42-1.87 (3 H, m) 142

0.80 294.40 ¹H NMR (400 MHz, MeOD- d₄) δ ppm 8.54 (1 H, d, J = 1.01 Hz),6.83 (1 H, br.s.), 4.04 (1 H, d, J = 10.32 Hz), 3.73 (1 H, d, J = 10.32Hz), 3.04-3.25 (2 H, m), 2.69- 2.97 (4 H, m), 1.96-2.18 (2 H, m),1.43-1.84 (3 H, m) 143

1.60 330.28 ¹H NMR (500 MHz, DMSO- D6) δ ppm 11.95 (s, 1 H), 7.54 (s, 1H), 7.35 (s, 1 H), 7.22 (s, 1 H), 7.04 (s, 1 H), 6.09 (s, 1 H), 3.66 (s,1 H), 3.39 (d, J = 7.02 Hz, 1 H), 3.04 (s, 1 H), 2.99 (s, 1 H), 2.84 (s,2 H), 2.67 (s, 3 H), 2.02 (s, 1 H), 1.92 (s, 1 H), 1.59 (s, 2 H), 1.51(s, 1 H) 144

1.00 326.30 ¹H NMR (400 MHz, MeOD- d₄) δ ppm 8.47 (1 H, s), 7.30- 7.79(1 H, m), 6.28 (1 H, br. s.), 4.02 (1 H, d, J = 10.32 Hz), 3.71 (1 H, d,J = 10.32 Hz), 3.16-3.25 (1 H, m), 3.04- 3.13 (1 H, m), 2.85-2.99 (2 H,m), 2.70-2.86 (2 H, m), 1.94- 2.20 (2 H, m), 1.49-1.84 (3 H, m). M.P.185-90° C. 145

1.16 344.30 ¹H NMR (400 MHz, MeOD- d₄) δ ppm 7.06 (1 H, s), 3.96 (1 H,d, J = 9.82 Hz), 3.65 (1 H, d, J = 10.07 Hz), 3.18-3.26 (1 H, m),3.05-3.13 (1 H, m), 2.87- 2.98 (2 H, m), 2.70-2.86 (5 H, m), 2.57 (3 H,s), 2.03-2.20 (2 H, m), 1.51-1.85 (3 H, m) 146

1.20 309.30 ¹H NMR (400 MHz, MeOD- d₄) δ ppm 8.46 (1 H, d, J = 8.31 Hz),8.06 (1 H, d, J = 6.04 Hz), 7.58-7.78 (2 H, m), 7.51 (1 H, td, J = 7.68,1.26 Hz), 7.25 (1 H, d, J = 6.04 Hz), 3.99 (1 H, d, J = 9.82 Hz), 3.67(1 H, d, J = 9.82 Hz), 3.23 (1 H, s), 3.04- 3.13 (1 H, m), 2.89-2.99 (2H, m), 2.71-2.88 (2 H, m), 2.04-2.27 (2 H, m), 1.46- 1.85 (3 H, m) 147

0.98 310.30 ¹H NMR (400 MHz, MeOD- d₄) δ ppm 8.72 (1 H, s), 8.46 (1 H,d, J = 7.81 Hz), 7.72-7.88 (2 H, m), 7.56 (1 H, ddd, J = 8.25, 6.86,1.26 Hz), 4.11 (1 H, d, J = 10.32 Hz), 3.80 (1 H, d, J = 10.32 Hz),3.09-3.17 (1 H, m), 2.97 (2 H, t, J = 7.43 Hz), 2.76-2.89 (2 H, m),2.04- 2.26 (2 H, m), 1.50-1.87 (3 H, m) 148

0.81 285.30 ¹H NMR (400 MHz, MeOD- d₄) δ ppm 8.64 (1 H, d, J = 1.26 Hz),8.28 (1 H, d, J = 1.26 Hz), 4.19 (1 H, d, J = 10.83 Hz), 3.97 (1 H, d, J= 11.08 Hz), 3.86 (1 H, dd, J = 14.60, 1.51 Hz), 3.72 (1 H, dd, J =14.86, 2.52 Hz), 3.44-3.56 (1 H, m), 3.31-3.43 (3 H, m), 2.49- 2.58 (1H, m), 2.28-2.42 (1 H, m, J = 13.53, 10.07, 3.56, 3.56, 3.27 Hz),1.91-2.18 (3 H, m) 149

0.73 290.30 ¹H NMR (400 MHz, MeOD- d₄) δ ppm 8.28 (2 H, s), 3.95 (1 H,d, J = 9.82 Hz), 3.86 (3 H, s), 3.65 (1 H, d, J = 9.82 Hz), 3.15- 3.24(1 H, m), 3.03-3.11 (1 H, m), 2.68-2.96 (4 H, m), 1.97-2.19 (2 H, m),1.49- 1.85 (3 H, m) 150

0.90 320.40 ¹H NMR (400 MHz, MeOD- d₄) δ ppm 5.87 (1 H, br.s.), 3.99 (1H, d, J = 10.32 Hz), 3.92 (3 H, s), 3.88 (3 H, s), 3.67 (1 H, d, J =10.32 Hz), 3.14-3.22 (1 H, m), 3.01- 3.10 (1 H, m), 2.70-2.94 (4 H, m),1.98-2.16 (2 H, m), 1.51- 1.82 (3 H, m) 151

1.15 366.30 ¹H NMR (400 MHz, MeOD- d₄) δ ppm 8.74 (2 H, s), 7.53 (2 H,d, J = 8.81 Hz), 7.02 (2 H, d, J = 8.81 Hz), 4.01 (1 H, d, J = 10.07Hz), 3.81 (3 H, s), 3.71 (1 H, d, J = 10.07 Hz), 3.26 (1 H, s),3.08-3.18 (1 H, m), 2.73-3.03 (4 H, m), 2.16 (2 H, br.s.), 1.51-1.90 (3H, m) 152

1.27 350.40 ¹H NMR (400 MHz, MeOD- d₄) δ ppm 8.78 (2 H, s), 7.27- 7.47(3 H, m), 7.20 (1 H, d, J = 7.30 Hz), 4.02 (1 H, d, J = 10.07 Hz), 3.71(1 H, d, J = 10.07 Hz), 3.24 (1 H, d, J = 15.11 Hz), 3.03-3.14 (1 H, m),2.70-3.00 (4 H, m), 2.40 (3 H, s), 2.03-2.22 (2 H, m), 1.53-1.84 (3 H,m) 153

2.13 362.28 ¹H NMR (400 MHz, MeOD- d₄) δ ppm 8.37 (1 H, s), 8.24 (1 H,dd, J = 7.55, 1.51 Hz), 7.88 (1 H, s), 7.19-7.44 (3 H, m), 4.02 (1 H, d,J = 10.07 Hz), 3.71 (1 H, d, J = 10.07 Hz), 3.24 (1 H, d, J = 16.87 Hz),3.05-3.12 (1 H, m), 2.70- 2.99 (8 H, m), 2.05-2.21 (2 H, m), 1.48-1.84(3 H, m) 154

0.57 339.10 ¹H NMR (500 MHz, MeOD- d₄) δ ppm 8.07 (d, J = 5.49 Hz, 1 H),7.47-7.71 (m, 1 H), 7.13- 7.34 (m, 1 H), 3.91-4.06 (m, 1 H), 3.56-3.73(m, 1 H), 3.14- 3.24 (m, 1 H), 3.02-3.14 (m, 1 H), 2.73-3.01 (m, 4 H),1.98- 2.21 (m, 2 H), 1.58-1.85 (m, 3 H) 155

0.64 339.04 ¹H NMR (500 MHz, MeOD- d₄) δ ppm 7.45-7.58 (m, 1 H),7.04-7.16 (m, 1 H), 6.90 (d, J = 7.32 Hz, 1 H), 3.95-4.09 (m, 1 H),3.67-3.77 (m, 1 H), 3.18-3.28 (m, 1 H), 3.07- 3.17 (m, 1 H), 2.76-3.05(m, 4 H), 2.04-2.22 (m, 2 H), 1.50- 1.89 (m, 3 H) 156

1.47 388.40 ¹H NMR (500 MHz, MeOD- d₄) δ ppm 7.96-8.03 (1 H, m),7.88-7.95 (1 H, m), 7.75- 7.84 (1 H, m), 7.61-7.73 (1 H, m), 7.06 (1 H,d, J = 8.55 Hz), 4.01-4.11 (1 H, m), 3.69- 3.82 (1 H, m), 3.20-3.29 (1H, m), 3.09-3.19 (1 H, m), 2.76- 3.02 (4 H, m), 2.09-2.23 (2 H, m),1.58-1.87(3 H, m) 157

1.33 323.50 ¹H NMR (500 MHz, MeOD- d₄) δ ppm 7.99 (1 H, d, J = 8.55 Hz),7.77 (1 H, d, J = 8.55 Hz), 7.41-7.57 (2 H, m), 7.02 (1 H, d, J = 8.55Hz), 4.08 (1 H, d, J = 9.77 Hz), 3.76 (1 H, d, J = 9.77 Hz), 3.26 (1 H,d, J = 14.95 Hz), 3.08-3.17 (1 H, m), 2.78-3.02 (4 H, m), 2.49 (3 H, s),2.08-2.31 (2 H, m), 1.54-1.89 (3 H, m) 158

1.19 316.16 ¹H NMR (500 MHz, DMSO- D6) δ ppm 12.36 (s, 1 H), 7.98 (s, 1H), 7.19-7.27 (m, 1 H), 7.15 (d, J = 8.24 Hz, 1 H), 6.64- 6.71 (m, 1 H),3.80 (d, J = 7.63 Hz, 1 H), 3.54 (s, 1 H), 2.95-3.04 (m, 2 H), 2.78 (s,2 H), 2.66 (s, 2 H), 2.01 (s, 1 H), 1.93 (s, 1 H), 1.58 (s, 2 H), 1.46(s, 1 H) 159

1.40 316.16 ¹H NMR (500 MHz, DMSO- D6) δ ppm 12.20 (s, 1 H), 7.98 (s, 1H), 7.38 (dd, J = 8.55, 3.36 Hz, 1 H), 7.32 (d, J = 8.55 Hz, 1 H), 7.18(t, J = 8.85 Hz, 1 H), 3.81 (d, J = 8.85 Hz, 1 H), 3.55 (d, J = 8.55 Hz,1 H), 2.97- 3.05 (m, 2 H), 2.79 (s, 2 H), 2.68 (t, J = 7.32 Hz, 3 H),2.02 (s, 1 H), 1.92 (s, 1 H), 1.59 (d, J = 6.41 Hz, 2 H), 1.47 (d, J =8.85 Hz, 1 H) 160

0.83 260.27 ¹H NMR (400 MHz, MeOD) δ ppm 8.89 (1 H, br.s.), 8.80 (1 H,d, J = 5.79 Hz), 7.53 (1 H, br.s.), 3.91 (1 H, d, J = 10.83 Hz), 3.60 (1H, d, J = 10.83 Hz), 3.16-3.25 (1 H, m), 3.02- 3.12 (1 H, m), 2.68-2.99(4 H, m), 1.94-2.17 (2 H, m), 1.53-1.83 (3 H, m) 161

1.55 328.21 ¹H NMR (400 MHz, MeOD- d₄) δ ppm 8.35 (1 H, s), 4.01 (1 H,d, J = 10.07 Hz), 3.70 (1 H, d, J = 10.07 Hz), 3.20-3.27 (1 H, m),3.05-3.13 (1 H, m), 2.69-2.99 (4 H, m), 2.34 (3 H, s), 2.29 (3 H, s),2.01-2.22 (2 H, m), 1.51-1.83 (3 H, m) 162

1.85 354.25 ¹H NMR (500 MHz, DMSO- D6) δ ppm 11.75-12.09 (m, J = 14.95Hz, 1 H), 7.62 (d, J = 7.93 Hz, 2 H), 7.38-7.54 (m, J = 10.99 Hz, 1 H),6.95 (d, J = 6.71 Hz, 2 H), 6.13 (s, 1 H), 3.76-3.83 (m, 4 H), 3.74 (s,1 H), 3.38 (d, J = 2.75 Hz, 1 H), 2.98 (s, 1 H), 2.82 (s, 2 H),2.62-2.71 (m, 2 H), 2.00 (s, 1 H), 1.92 (s, 1 H), 1.58 (s, 2 H), 1.50(s, 1 H) 163

2.09 366.17 ¹H NMR (500 MHz, DMSO- D6) δ ppm 12.54 (s, 1 H), 8.05 (s, 1H), 7.97 (s, 1 H), 7.52- 7.60 (m, 2 H), 3.82 (s, 1 H), 3.58 (s, 1 H),3.01 (s, 2 H), 2.78 (s, 2 H), 2.64-2.70 (m, 2 H), 1.99-2.05 (m, 1 H),1.92 (s, 1 H), 1.58 (s, 2 H), 1.47 (s, 1 H) 164

2.12 366.17 ¹H NMR (500 MHz, DMSO- D6) δ ppm 12.54 (s, 1 H), 8.03 (s, 1H), 7.85 (d, J = 8.24 Hz, 1 H), 7.70 (s, 1 H), 7.26 (d, J = 8.24 Hz, 1H), 3.83 (d, J = 9.46 Hz, 1 H), 3.57 (d, J = 8.85 Hz, 1 H), 2.97-3.05(m, 2 H), 2.79 (s, 2 H), 2.67 (t, J = 7.48 Hz, 2 H), 2.03 (d, J = 2.44Hz, 1 H), 1.92 (s, 1 H), 1.59 (d, J = 5.80 Hz, 2 H), 1.46 (s, 1 H) 165

1.24 298.16 ¹H NMR (500 MHz, DMSO- D6) δ ppm 12.07 (s, 1 H), 8.02 (s, 1H), 7.63 (d, J = 7.63 Hz, 1 H), 7.27-7.36 (m, 2 H), 6.99 (t, J = 7.32Hz, 1 H), 3.82 (d, J = 9.46 Hz, 1 H), 3.56 (d, J = 8.85 Hz, 1 H), 3.00(s, 2 H), 2.79 (s, 2 H), 2.67 (t, J = 6.87 Hz, 2 H), 2.02 (d, J = 2.75Hz, 1 H), 1.93 (s, 1 H), 1.58 (s, 2 H), 1.47 (s, 1 H) 166

1.16 366.30 ¹H NMR (500 MHz, MeOD- d₄) δ ppm 8.53 (1 H, d, J = 5.19 Hz),8.02-8.15 (2 H, m), 7.39 (1 H, d, J = 5.19 Hz), 7.01- 7.11 (2 H, m),4.06 (1 H, d, J = 10.07 Hz), 3.89 (3 H, s), 3.74 (1 H, d J, 10.07 Hz),3.28 (1 H, d, J = 14.95 Hz), 3.13 (1 H, d, J = 14.95 Hz), 2.73-3.02 (4H, m), 2.07- 2.25 (2 H, m), 1.54-1.86 (3 H, m) 167

1.25 344.40 ¹H NMR (500 MHz, MeOD- d₄) δ ppm 8.48 (1 H, s), 4.05 (1 H,d, J = 10.07 Hz), 3.74 (1 H, d, J = 10.07 Hz), 3.26 (1 H, s), 3.14 (1 H,d, J = 14.65 Hz), 2.76-3.02 (4 H, m), 2.59 (3 H, s), 2.46 (3 H, s),2.09-2.23 (2 H, m), 1.57-1.89 (3 H, m) 168

1.73 390.20 ¹H NMR (500 MHz, MeOD- d₄) δ ppm 9.27 (1 H, s), 8.14 (1 H,d, J = 2.14 Hz), 7.93 (1 H, dd, J = 8.85, 1.83 Hz), 7.78 (1 H, d, J =8.85 Hz), 4.11 (1 H, d, J = 10.07 Hz), 3.80 (1 H, d, J = 10.07 Hz), 3.28(1 H, s), 3.15 (1 H, d, J = 14.95 Hz), 2.78-3.02 (4 H, m), 2.05- 2.25 (2H, m), 1.52-1.88 (3 H, m) 169

0.71 260.40 ¹H NMR (500 MHz, MeOD- d₄) δ ppm 8.73 (1 H, s), 8.59 (2 H,br.s.), 3.86 (1 H, d, J = 9.77 Hz), 3.56 (1 H, d, J = 9.77 Hz),3.18-3.26 (1 H, m), 3.05- 3.12 (1 H, m), 2.72-2.99 (4 H, m), 2.17 (1 H,br.s.), 2.01 (1 H, br.s.), 1.54-1.86 (3 H, m) 170

0.78 290.30 ¹H NMR (400 MHz, CDCl₃) δ ppm 8.57 (1 H, br.s.), 7.97 (1 H,d, J = 1.51 Hz), 7.80 (1 H, d, J = 1.26 Hz), 3.90 (3 H, s), 3.87 (1 H,d, J = 9.06 Hz), 3.54 (1 H, d, J = 9.06 Hz), 3.32 (1 H, dd, J = 14.86,1.76 Hz), 2.69-3.04 (5 H, m), 2.13-2.23 (1 H, m), 2.06-2.11 (1 H, m),1.63- 1.76 (1 H, m), 1.41-1.61 (2 H, m) 171

1.06 368.40 ¹H NMR (400 MHz, MeOD- d₄) δ ppm 3.99 (1 H, d, J = 10.07Hz), 3.68 (1 H, d, J = 10.07 Hz), 3.15-3.24 (1 H, m), 3.02-3.10 (1 H,m), 2.68- 2.96 (4 H, m), 2.53 (6 H, s), 2.02-2.19 (2 H, m), 1.46- 1.83(3 H, m) 172

0.89 304.25 ¹H NMR (400 MHz, MeOD- d₄) δ ppm 6.22 (1 H, s), 3.99 (1 H,d, J = 10.07 Hz), 3.89 (3 H, s), 3.67 (1 H, d, J = 10.07 Hz), 3.15-3.25(1 H, m), 3.00- 3.11 (1 H, m), 2.67-2.97 (4 H, m), 2.32 (3 H, s),2.00-2.19 (2 H, m), 1.42-1.83 (3 H, m) 173

1.07 371.17 ¹H NMR (500 MHz, DMSO- D6) δ ppm 8.57 (s, 1 H), 7.46- 7.54(m, 6 H), 7.31 (t, J = 7.93 Hz, 2 H), 6.87 (dd, J = 8.24, 2.44 Hz, 2 H),3.87 (d, J = 9.77 Hz, 2 H), 3.82 (s, 6 H), 3.61 (d, J = 9.77 Hz, 2 H),3.03 (s, 4 H), 2.75-2.84 (m, 4 H), 2.68 (t, J = 7.63 Hz, 4 H), 2.06 (s,2 H), 1.93 (s, 2 H), 1.56-1.64 (m, 4 H), 1.50 (dd, J = 9.46, 2.44 Hz, 2H) 174

1.32 363.44 ¹H NMR (500 MHz, DMSO- d₆) δ ppm 8.73-8.93 (m, 1 H), 7.73(s, 1 H), 7.20 (s, 1 H), 3.91 (d, J = 9.77 Hz, 1 H), 3.66 (d, J = 10.07Hz, 1 H), 3.05 (s, 2 H), 2.74-2.89 (m, 1 H), 2.68 (t, J = 7.63 Hz, 1 H),2.54 (s, 3 H), 2.09 (br.s., 2 H), 1.83- 1.98 (m, 1 H), 1.42-1.69 (m, 2H) 175

0.40 274.26 ¹H NMR (400 MHz, MeOD- d₄) δ ppm 8.36 (1 H, d, J = 5.04 Hz),6.82 (1 H, d, J = 5.04 Hz), 3.98 (1 H, d, J = 10.07 Hz), 3.67 (1 H, d, J= 10.07 Hz), 3.17-3.25 (1 H, m), 3.03- 3.10 (1 H, m), 2.70-2.96 (4 H,m), 2.41 (3 H, s), 1.98-2.22 (2 H, m), 1.44-1.87 (3 H, m) 176

0.72 288.25 ¹H NMR (400 MHz, MeOD- d₄) δ ppm 6.72 (1 H, s), 3.98 (1 H,d, J = 10.07 Hz), 3.67 (1 H, d, J = 9.82 Hz), 3.18-3.24 (1 H, m),3.02-3.12 (1 H, m), 2.65-2.96 (4 H, m), 2.36 (6 H, s), 2.02-2.21 (2 H,m), 1.45- 1.83 (3 H, m) 177

2.13 362.28 ¹H NMR (400 MHz, MeOD- d₄) δ ppm 8.37 (1 H, s), 8.24 (1 H,dd, J = 7.55, 1.51 Hz), 7.88 (1 H, s), 7.19-7.44 (3 H, m), 4.02 (1 H, d,J = 10.07 Hz), 3.71 (1 H, d, J = 10.07 Hz), 3.24 (1 H, d, J = 16.87 Hz),3.05-3.12 (1 H, m), 2.70- 2.99 (8 H, m), 2.05-2.21 (2 H, m), 1.48-1.84(3 H, m) 178

1.31 370.18 ¹H NMR (400 MHz, MeOD- d₄) δ ppm 8.32 (1 H, s), 3.94- 4.03(4 H, m), 3.68 (1 H, d, J = 10.07 Hz), 3.15-3.26 (1 H, m), 3.01-3.12 (1H, m), 2.68- 2.96 (4 H, m), 2.01-2.16 (2 H, m), 1.51-1.84 (3 H, m) 179

1.87 353.28 ¹H NMR (500 MHz, MeOD- d₄) δ ppm 7.83 (1 H, s), 7.63- 7.76(1 H, m), 7.19 (1 H, dd, J = 9.00, 2.90 Hz), 7.09 (1 H, d, J = 2.75 Hz),3.93-4.02 (1 H, m), 3.84-3.93 (3 H, m), 3.69 (1 H, d, J = 9.77 Hz), 3.26(1 H, d, J = 14.65 Hz), 3.11 (1 H, d, J = 14.95 Hz), 2.70-3.01 (4 H, m),2.39 (3 H, s), 2.06-2.27 (2 H, m), 1.57-1.85 (3 H, m) 180

1.94 350.30 ¹H NMR (400 MHz, MeOD- d₄) δ ppm 7.91-8.15 (2 H, m),7.38-7.53 (3 H, m), 7.31 (1 H, s), 4.02 (1 H, d, J = 10.07 Hz), 3.70 (1H, d, J = 10.07 Hz), 3.17-3.26 (1 H, m), 3.02- 3.14 (1 H, m), 2.66-2.98(4 H, m), 2.48 (3 H, s), 2.03-2.20 (2 H, m), 1.49-1.83 (3 H, m) 181

1.17 336.40 ¹H NMR (400 MHz, MeOD- d₄) δ ppm 8.55 (1 H, d, J = 5.29 Hz),8.08 (2 H, dd, J = 6.67, 2.90 Hz), 7.44-7.53 (3 H, m), 7.40 (1 H, d, J =5.29 Hz), 4.01 (1 H, d, J = 10.07 Hz), 3.70 (1 H, d, J = 10.07 Hz),3.20-3.28 (1 H, m), 3.04-3.14 (1 H, m), 2.67-2.99 (4 H, m), 2.05- 2.24(2 H, m), 1.49-1.85 (3 H, m) 182

0.42 289.22 ¹H NMR (400 MHz, MeOD- d₄) δ ppm 4.02 (1 H, d, J = 10.32Hz), 3.71 (1 H, d, J = 10.32 Hz), 3.23 (1 H, d, J = 15.36 Hz), 3.03-3.13(1 H, m), 2.69-2.98 (4 H, m), 2.54 (3 H, s), 2.48 (3 H, s), 2.01- 2.21(2 H, m), 1.41-1.85 (3 H, m) 183

1.19 382.19 ¹H NMR (500 MHz, DMSO- D6) δ ppm 12.37 (s, 1 H), 8.01 (s, 1H), 7.53 (s, 1 H), 7.45 (d, J = 9.16 Hz, 1 H), 7.28 (d, J = 8.85 Hz, 1H), 3.82 (d, J = 9.16 Hz, 1 H), 3.57 (d, J = 9.46 Hz, 1 H), 3.00 (s, 2H), 2.78 (s, 2 H), 2.67 (t, J = 7.48 Hz, 2 H), 1.96-2.04 (m, 1 H), 1.91(d, J = 8.85 Hz, 1 H), 1.55- 1.63 (m, 2 H), 1.47 (d, J = 7.02 Hz, 1 H)184

0.75 274.30 ¹H NMR (400 MHz, CDCl₃) δ ppm 9.08 (1 H, br.s.), 8.12 (1 H,s), 7.85 (1 H, s), 3.89 (1 H, d, J = 9.32 Hz), 3.55 (1 H, d, J = 9.32Hz), 3.28 (1 H, dd, J = 14.86, 1.26 Hz), 2.62-2.97 (5 H, m), 2.35 (3 H,s), 2.06- 2.17 (1 H, m, J = 13.13, 9.82, 3.53, 3.38, 3.38 Hz), 2.04 (1H, br.s.), 1.59-1.73 (1 H, m), 1.37-1.57 (2 H, m) 185

0.75 274.30 ¹H NMR (400 MHz, CDCl₃) δ ppm 9.29 (1 H, br.s.), 7.90 (2 H,br.s.), 3.90 (1 H, d, J = 9.32 Hz), 3.55 (1 H, d, J = 9.06 Hz), 3.35 (1H, d, J = 14.86 Hz), 2.65-3.08 (5 H, m), 2.56 (3 H, s), 2.12-2.27 (1 H,m), 2.08 (1 H, br.s.), 1.62- 1.77 (1 H, m), 1.38-1.61 (2 H, m) 186

0.79 288.30 ¹H NMR (400 MHz, CDCl₃) δ ppm 9.16 (1 H, br.s.), 7.78 (1 H,s), 3.88 (1 H, d, J = 9.06 Hz), 3.53 (1 H, d, J = 9.32 Hz), 3.34 (1 H,dd, J = 14.86, 2.01 Hz), 2.64-3.07 (5 H, m), 2.55 (3 H, s), 2.38 (3 H,s), 2.14- 2.25 (1 H, m), 2.04-2.11 (1 H, m), 1.68 (1 H, dddd, J = 13.94,9.66, 4.53, 4.34 Hz), 1.41- 1.61 (2 H, m) 187

0.58 293.06 ¹H NMR (500 MHz, DMSO- d₆) d ppm 3.73-3.87 (m, 1 H),3.47-3.58 (m, 1 H), 2.98 (s, 2 H), 2.71-2.85 (m, 2 H), 2.65 (t, J = 7.78Hz, 2 H), 2.18 (s, 3 H), 2.11 (s, 3 H), 2.00 (br.s., 1 H), 1.80-1.96 (m,1 H), 1.57 (dd, J = 8.24, 2.75 Hz, 3 H) 188

0.86 325.20 ¹H NMR (500 MHz, DMSO- d₆) δ ppm 8.07 (d, J = 7.32 Hz, 2 H),7.42 (d, J = 7.63 Hz, 3 H), 3.87 (s, 1 H), 3.55-3.70 (m, 1 H), 3.02 (s,2 H), 2.72-2.88 (m, 2 H), 2.68 (s, 2 H), 1.98- 2.10 (m, 1 H), 1.81-1.97(m, 1 H), 1.40-1.68 (m, 3 H) 189

1.04 355.24 ¹H NMR (500 MHz, DMSO- d₆) δ ppm 7.36-7.47 (m, 3 H),7.24-7.34 (m, 2 H), 3.84 (d, J = 10.07 Hz, 1 H), 3.58 (d, J = 9.77 Hz, 1H), 3.01 (s, 2 H), 2.71-2.87 (m, 2 H), 2.66 (t, J = 7.63 Hz, 2 H), 2.32(s, 3 H), 2.04 (br.s., 1 H), 1.83-1.98 (m, 1 H), 1.43-1.64 (m, 3 H) 190

0.26 262.11 ¹H NMR (500 MHz, DMSO- d₆) d ppm 7.43 (br.s., 1 H),5.56-5.76 (m, 1 H), 3.58- 3.83 (m, 4 H), 3.37-3.52 (m, 1 H), 2.94 (s, 2H), 2.68-2.88 (m, 2 H), 2.60-2.68 (m, 2 H), 1.94 (br.s., 2 H), 1.37-1.65(m, 3 H) 191

1.65 350.30 ¹H NMR (400 MHz, MeOD) δ ppm 8.43 (1 H, s), 7.58 (2 H, dd, J= 7.55, 1.76 Hz), 7.39- 7.52 (3 H, m), 3.96 (1 H, d, J = 10.07 Hz), 3.66(1 H, d, J = 9.82 Hz), 3.25 (1 H, d, J = 16.12 Hz), 3.05-3.14 (1 H, m),2.88-2.98 (2 H, m), 2.68- 2.87 (2 H, m), 2.24 (3 H, s), 2.03-2.17 (2 H,m), 1.45- 1.84 (3 H, m) 192

1.02 337.28 ¹H NMR (400 MHz, MeOD) δ ppm 8.64 (2 H, d, J = 5.29 Hz),8.40 (1 H, d, J = 7.81 Hz), 7.86- 7.97 (1 H, m), 7.80 (1 H, d, J = 5.04Hz), 7.47 (1 H, dd, J = 6.55, 5.04 Hz), 4.03 (1 H, d, J = 10.07 Hz),3.74 (1 H, d, J = 10.07 Hz), 3.29 (1 H, d, J = 1.51 Hz), 3.12-3.22 (1 H,m), 2.99 (2 H, t, J = 7.68 Hz), 2.78-2.92 (2 H, m), 2.03- 2.26 (2 H, m),1.45-1.88 (3 H, m) 193

NA NA ¹H NMR (400 MHz, MeOD) δ ppm 8.69 (1 H, s), 7.61-7.78 (2 H, m),7.34-7.56 (3 H, m), 3.99 (1 H, d, J = 10.07 Hz), 3.68 (1 H, d, J = 10.32Hz), 3.15-3.25 (1 H, m), 3.02- 3.11 (1 H, m), 2.92 (2 H, t, J = 7.55Hz), 2.69-2.86 (2 H, m), 2.01-2.20 (2 H, m), 1.47- 1.81 (3 H, m) 194

NA NA ¹H NMR (400 MHz, MeOD) δ ppm 9.24 (1 H, d, J = 1.51 Hz), 8.60-8.68(2 H, m), 8.53 (1 H, dt, J = 7.99, 1.92 Hz), 7.40- 7.64 (2 H, m), 4.05(1 H, d, J = 10.32 Hz), 3.76 (1 H, d, J = 10.07 Hz), 3.33-3.40 (1 H, m),3.17-3.26 (1 H, m), 2.82- 3.09 (4 H, m), 2.09-2.31 (2 H, m), 1.55-1.91(3 H, m) 195

1.41 403.36 ¹H NMR (400 MHz, MeOD) δ ppm 8.65 (1 H, s), 8.40 (1 H, s),8.17 (1 H, s), 7.25-7.47 (5 H, m), 4.04 (1 H, d, J = 10.32 Hz), 3.73 (1H, d, J = 10.32 Hz), 3.17-3.27 (1 H, m), 3.04- 3.13 (1 H, m), 2.63-3.00(4 H, m), 2.00-2.22 (2 H, m), 1.48-1.87 (3 H, m) 196

1.69 364.36 ¹H NMR (400 MHz, MeOD) δ ppm 8.33 (1 H, s), 8.16 (1 H, dd, J= 7.81, 1.51 Hz), 7.30- 7.44 (1 H, m), 7.08 (1 H, t, J = 7.55 Hz), 6.95(1 H, d, J = 8.31 Hz), 5.16 (2 H, s), 4.02 (1 H, d, J = 9.82 Hz), 3.71(1 H, d, J = 10.07 Hz), 3.18-3.26 (1 H, m), 3.04-3.13 (1 H, m), 2.93 (2H, t, J = 7.68 Hz), 2.71- 2.86 (2 H, m), 2.01-2.23 (2 H, m), 1.50-1.83(3 H, m) 197

0.53 277.13 ¹H NMR (500 MHz, DMSO- D6) δ ppm 8.76 (s, 1 H), 8.15 (d, J =2.44 Hz, 1 H), 7.55 (s, 1 H), 6.83 (s, 1 H), 3.79 (s, 1 H), 3.54 (d, J =10.07 Hz, 1 H), 2.92-3.00 (m, 3 H), 2.70- 2.80 (m, 3 H), 2.66 (t, J =7.78 Hz, 3 H), 1.97 (s, 1 H), 1.88 (s, 1 H), 1.53-1.61 (m, 3 H), 1.41-1.49 (m, 1 H) 198

0.77 337.07 ¹H NMR (500 MHz, DMSO- d₆) δ ppm 8.26 (br.s., 1 H), 7.76(br.s., 1 H), 6.75 (br.s., 1 H), 3.81 (br.s., 1 H), 3.56 (d, J = 9.46Hz, 1 H), 2.85-3.10 (m, 2 H), 2.56-2.85 (m, 4 H), 1.97 (br.s., 2 H),1.36-1.67 (m, 3 H) 199

0.16 289.19 ¹H NMR (500 MHz, MeOD) δ ppm 7.90 (d, J = 6.10 Hz, 1 H),6.74-7.00 (m, 2 H), 3.93- 4.09 (m, 1 H), 3.88 (s, 3 H), 3.61-3.71 (m, 1H), 3.14- 3.25 (m, 1 H), 3.06 (d, J = 1.83 Hz, 1 H), 2.69-2.99 (m, 3 H),2.07 (br.s., 2 H), 1.74 (d, J = 8.24 Hz, 3 H), 1.18 (d, J = 6.41 Hz, 1H) 200

0.82 332.97 ¹H NMR (400 MHz, DMSO- d₆) δ ppm 7.71 (dd, J = 8.78, 2.76Hz, 1 H), 7.59 (dd, J = 8.91, 4.89 Hz, 1 H), 7.17 (td, J = 9.03, 2.76Hz, 1 H), 3.89 (d, J = 10.04 Hz, 1 H), 3.64 (d, J = 10.04 Hz, 1 H),2.97-3.13 (m, 2 H), 2.75- 2.88 (m, 2 H), 2.67 (t, J = 7.65 Hz, 2 H),2.02-2.12 (m, 1 H), 1.81-1.98 (m, 1 H), 1.36- 1.69 (m, 3 H) 201

1.16 314.35 ¹H NMR (400 MHz, MeOD) δ ppm 8.20 (1 H, s), 3.96 (1 H, d, J= 10.07 Hz), 3.65 (1 H, d, J = 9.82 Hz), 3.20 (1 H, d), 3.06 (1 H, d),2.91 (2 H, t, J = 7.43 Hz), 2.71-2.84 (4 H, m), 2.66 (2 H, t, J = 6.04Hz), 1.98-2.21 (2 H, m), 1.43-1.94 (7 H, m) 202

0.69 300.29 ¹H NMR (400 MHz, MeOD) δ ppm 8.30 (1 H, s), 3.97 (1 H, d, J= 9.82 Hz), 3.66 (1 H, d, J = 10.07 Hz), 3.21 (1 H, d), 3.06 (1 H, d),2.74-2.97 (8 H, m), 2.11 (4 H, dq, J = 7.68, 7.51 Hz), 1.39-1.85 (3 H,m) 203

1.19 322.25 ¹H NMR (400 MHz, MeOD) δ ppm 4.00 (1 H, d, J = 10.07 Hz),3.69 (1 H, d, J = 10.07 Hz), 3.22 (1 H, d, J = 14.60 Hz), 3.03-3.14 (1H, m), 2.69- 2.97 (4 H, m), 2.46 (3 H, s), 2.26 (3 H, s), 2.03-2.17 (2H, m), 1.51-1.84 (3 H, m) 204

0.67 328.28 ¹H NMR (400 MHz, MeOD) δ ppm 8.92 (1 H, s), 4.05 (1 H, d, J= 10.32 Hz), 3.75 (1 H, d, J = 10.32 Hz), 3.24 (1 H, d, J = 1.26 Hz),3.06-3.17 (1 H, m), 2.75-3.03 (6 H, m), 2.56- 2.68 (2 H, m), 2.13 (4 H,ddd, J = 12.72, 6.30, 6.17 Hz), 1.54- 1.84 (3 H, m) 205

0.15 284.10 ¹H NMR (500 MHz, DMSO- D6) δ ppm 9.01 (s, 1 H), 8.40 (d, J =4.88 Hz, 1 H), 7.21 (s, 1 H), 7.16 (s, 1 H), 3.84 (s, 1 H), 3.59 (d, J =10.07 Hz, 1 H), 2.94-3.02 (m, 3 H), 2.70- 2.79 (m, 3 H), 2.62-2.68 (m, 3H), 1.99 (s, 1 H), 1.87 (s, 1 H), 1.57 (d, J = 3.05 Hz, 2 H), 1.56 (s, 1H), 1.41-1.49 (m, 1 H) 206

0.78 366.10 ¹H NMR (500 MHz, DMSO- D6) δ ppm 12.63 (s, 1 H), 7.95 (d, J= 7.63 Hz, 2 H), 7.68 (d, J = 6.71 Hz, 1 H), 7.16 (t, J = 7.32 Hz, 1 H),3.84 (s, 1 H), 3.60 (s, 1 H), 3.03 (s, 2 H), 2.80 (s, 2 H), 2.64-2.72(m, 2 H), 2.05 (s, 1 H), 1.92 (s, 1 H), 1.60 (d, J = 8.24 Hz, 2 H), 1.48(s, 1 H) 207

0.77 335.17 ¹H NMR (500 MHz, DMSO- D6) δ ppm 9.05 (s, 1 H), 8.52 (d, J =2.44 Hz, 1 H), 7.91 (s, 1 H), 7.66 (d, J = 7.63 Hz, 2 H), 7.47 (t, J =7.63 Hz, 2 H), 7.36 (t, J = 7.32 Hz, 1 H), 6.87 (s, 1 H), 3.84 (s, 1 H),3.59 (d, J = 10.07 Hz, 1 H), 2.99 (s, 2 H), 2.72-2.81 (m, 2 H), 2.63-2.71 (m, 3 H), 1.99 (s, 1 H), 1.90 (s, 1 H), 1.59 (s, 2 H), 1.42-1.50(m, 1 H) 208

0.63 342.25 ¹H NMR (500 MHz, DMSO- D6) δ ppm 9.30 (s, 1 H), 7.19 (d, J =8.55 Hz, 1 H), 6.94 (d, J = 2.44 Hz, 1 H), 6.69 (dd, J = 8.55, 2.14 Hz,1 H), 3.92 (d, J = 10.07 Hz, 1 H), 3.75 (s, 3 H), 3.66 (d, J = 9.77 Hz,1 H), 3.54 (s, 3 H), 2.99-3.07 (m, 2 H), 2.79 (t, J = 7.78 Hz, 2 H),2.68 (t, J = 7.78 Hz, 2 H), 2.02- 2.07 (m, 1 H), 1.89 (dd, J = 6.41,3.36 Hz, 1 H), 1.56- 1.64 (m, 2 H), 1.44-1.52 (m, 1 H) 209

0.96 300.34 ¹H NMR (400 MHz, MeOD) d ppm 8.27 (1 H, d, J 5.04 Hz), 6.78(1 H, d, J = 5.29 Hz), 3.98 (1 H, d, J = 10.07 Hz), 3.66 (1 H, d, J =10.07 Hz), 3.21 (1 H, d), 3.06 (1 H, d), 2.64-2.99 (4 H, m), 2.02-2.17(2 H, m), 1.92-2.05 (1 H, m), 1.54- 1.82 (3 H, m), 0.92-1.11 (4 H, m)210

1.64 378.23 ¹H NMR (400 MHz, MeOD) d ppm 8.42 (1 H, s), 3.97 (1 H, d, J= 10.07 Hz), 3.66 (1 H, d, J = 10.07 Hz), 3.20 (1 H, d), 3.06 (1 H, d),2.63-2.97 (4 H, m), 2.35-2.50 (1 H, m), 1.99- 2.16 (2 H, m), 1.50-1.83(3 H, m), 0.98-1.24 (4 H, m) 211

0.64 342.18 ¹H NMR (500 MHz, DMSO- D6) δ ppm 7.98 (s, 1 H), 7.46 (t, J =7.93 Hz, 1 H), 6.91 (d, J = 5.49 Hz, 1 H), 6.59-6.65 (m, 1 H), 3.82-3.88(m, 6 H), 3.82 (s, 2 H), 3.55 (s, 1 H), 3.00 (s, 2 H), 2.78 (s, 2 H),2.67 (d, J = 6.71 Hz, 2 H), 2.01 (s, 1 H), 1.91 (s, 1 H), 1.59 (s, 2 H),1.46 (s, 1 H) 212

0.63 342.25 ¹H NMR (500 MHz, DMSO- D6) δ ppm 7.94 (s, 1 H), 7.37 (d, J =9.16 Hz, 1 H), 7.02 (d, J = 9.46 Hz, 1 H), 6.99 (d, J = 1.83 Hz, 1 H),3.87 (s, 3 H), 3.82 (d, J = 9.46 Hz, 1 H), 3.78 (s, 3 H), 3.56 (d, J =9.16 Hz, 1 H), 3.00 (s, 2 H), 2.78 (s, 2 H), 2.63-2.70 (m, 2 H), 2.01(s, 1 H), 1.91 (s, 1 H), 1.58 (s, 2 H), 1.46 (s, 1 H) 213

0.35 294.25 ¹H NMR (400 MHz, MeOD) d ppm 8.51 (2 H, s), 4.00 (1 H, d, J= 10.32 Hz), 3.69 (1 H, d, J = 10.32 Hz), 3.22 (1 H, d), 3.08 (1 H, d),2.70-2.98 (4 H, m), 2.01-2.21 (2 H, m), 1.50- 1.84 (3 H, m) 214

0.36 293.14 ¹H NMR (500 MHz, DMSO- D6) δ ppm 8.80 (s, 1 H), 8.19 (s, 1H), 7.66 (s, 1 H), 6.80 (s, 1 H), 3.81 (s, 1 H), 3.56 (d, J = 10.07 Hz,1 H), 2.92-3.01 (m, 2 H), 2.70-2.79 (m, 2 H), 2.62-2.68 (m, 2 H), 1.97(s, 1 H), 1.87 (s, 1 H), 1.57 (d, J = 7.32 Hz, 2 H), 1.40-1.49 (m, 1 H)215

0.35 293.14 ¹H NMR (500 MHz, DMSO- D6) δ ppm 9.01 (s, 1 H), 8.17 (d, J =5.49 Hz, 2 H), 6.97 (s, 2 H), 6.83 (s, 1 H), 3.83 (s, 2 H), 3.57 (d, J =10.38 Hz, 2 H), 2.93-3.01 (m, 3 H), 2.74- 2.82 (m, 3 H), 2.73 (s, 1 H),2.66 (t, J = 7.63 Hz, 3 H), 1.98 (s, 2 H), 1.87 (s, 2 H), 1.53- 1.62 (m,3 H), 1.41-1.49 (m, 2 H) 216

0.82 318.30 ¹H NMR (400 MHz, CDCl₃) δ ppm 8.56 (1 H, br.s.), 7.94 (1 H,d, J = 1.26 Hz), 7.72 (1 H, d, J = 1.26 Hz), 5.14 (1 H, spt, J = 6.13Hz), 3.85 (1 H, d, J = 9.06 Hz), 3.52 (1 H, d, J = 9.06 Hz), 3.30 (1 H,dd, J = 14.86, 1.51 Hz), 2.67-3.03 (5 H, m), 2.11-2.26 (1 H, m, J =13.17, 9.84, 3.65, 3.42, 3.42 Hz), 2.07 (1 H, br.s.), 1.62- 1.75 (1 H,m), 1.41-1.59 (2 H, m), 1.30 (6 H, d, J = 6.30 Hz) 217

0.18 342.19 ¹H NMR (400 MHz, DMSO- D6) δ ppm 8.09 (s, 1 H), 7.53 (s, 1H), 3.80 (s, 1 H), 3.54 (d, J = 10.32 Hz, 1 H), 3.07-3.18 (m, 1 H),2.91-3.01 (m, 3 H), 2.75 (d, J = 8.31 Hz, 2 H), 2.60- 2.71 (m, 2 H),2.19 (q, J = 8.90 Hz, 1 H), 2.01-2.12 (m, 4 H), 1.94 (s, 1 H), 1.83 (d,J = 15.11 Hz, 2 H), 1.56 (s, 3 H), 1.43 (s, 1 H)

Example 218(R)—N-(6-(methoxymethyl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 6-(Methoxymethyl)pyrimidin-4-ol

To a solution of methyl 4-methoxy-3-oxobutanoate (3.54 mL, 26.5 mmol) inmethanol (30 ml) was added formamidine acetate (3.07 g, 29.2 mmol) andsodium methoxide (13 mL, 58.4 mmol). The mixture was then heated toreflux for 18 hours and cooled to ambient temperature, thenconcentrated. The residue was taken up in water and the pH adjusted to 7with 1N HCl. The aqueous mixture was extracted with chloroform. Thecombined organic layers were dried over magnesium sulfate, filtered andconcentrated to afford 6-(methoxymethyl)pyrimidin-4-ol (1.38 g, 9.85mmol, 37.1% yield). MS (LC/MS) R.T.=0.19; [M+H]⁺=141.20.

Step B: 4-Chloro-6-(methoxymethyl)pyrimidine

6-(Methoxymethyl)pyrimidin-4-ol (1.38 g, 9.85 mmol) was taken up indichloromethane (14 ml) and phosphorous oxychloride (9 mL, 97 mmol) wasadded at ambient temperature. The mixture was stirred at ambient for 18h and concentrated. The residue was taken up in ice-water and the pH wasadjusted to 7 with 1N sodium hydroxide. The mixture was extracted withchloroform and dried over sodium sulfate, filtered and concentrated invacuo. The residue was purified by column chromatography (5-10% ethylacetate/chloroform) to afford 4-chloro-6-(methoxymethyl)pyrimidine (1.2g, 7.57 mmol, 77% yield) as a pale yellow oil, which solidified onstanding. 1H NMR (400 MHz, CDCl₃) δ ppm 8.88 (1H, d, J=1.01 Hz), 7.52(1H, d, J=1.01 Hz), 4.53 (2H, s), 3.50 (3H, s). MS (LC/MS) R.T.=0.98;[M+H]⁺=159.10.

Step C: 6-(Methoxymethyl)pyrimidin-4-amine

A mixture of 4-chloro-6-(methoxymethyl)pyrimidine (1.2 g, 7.57 mmol) andammonium hydroxide (20 ml) was heated in a sealed tube for 3 hours. Themixture was cooled to ambient temperature and concentrated. The residuewas triturated with ether to afford 6-(methoxymethyl)pyrimidin-4-amine(0.50 g, 3.59 mmol, 48% yield) as a pale yellow solid. ¹H NMR (400 MHz,CDCl₃) δ ppm 8.47 (1H, s), 6.55 (1H, s), 5.12 (2H, br. s.), 4.38 (2H,s), 3.45 (3H, s). MS (LC/MS) R.T.=0.42; [M+H]⁺=140.20.

Step D: 4-Isothiocyanato-6-(methoxymethyl)pyrimidine

To a bright orange solution of 1,1′-thiocarbonyldipyridin-2(1H)-one(0.84 g, 3.59 mmol) was in dichloromethane at ambient temperature wasadded 6-(methoxymethyl)pyrimidin-4-amine (0.5 g, 3.59 mmol). The orangesolution was stirred at ambient temperature for 18 h. The solution waspurified by column chromatography (0-40% ethyl acetate/hexanes) toafford 4-isothiocyanato-6-(methoxymethyl)pyrimidine (0.32 g, 1.77 mmol,49% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.91 (1H, d,J=1.26 Hz), 7.19 (1H, d, J=1.01 Hz), 4.52 (2H, s), 3.49 (3H, s). MS(LC/MS) R.T.=1.39; [M+H]⁺=182.10.

Step E:(R)—N-(6-(Methoxymethyl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.39 g, 1.71mmol) in dimethylformamide was added cesium carbonate (1.39 g, 4.28mmol) and 4-isothiocyanato-6-(methoxymethyl)pyrimidine (0.31 g, 1.71mmol). The suspension was stirred at ambient temperature for 15 min. Tothe reaction mixture was added N,N′-diisopropylcarbodiimide (0.80 mL,5.13 mmol) and the mixture was stirred overnight then concentrated. Theresidue was purified by column chromatography (5-25% 9:1methanol/ammonium hydroxide in ethyl acetate) to afford(R)—N-(6-(methoxymethyl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.18 g, 0.58 mmol, 34% yield) as a yellow solid. ¹H NMR (400 MHz,MeOD-d₄) δ ppm 8.65 (1H, d, J=1.01 Hz), 6.92 (1H, br. s.), 4.40 (3H, s),4.03 (1H, d, J=10.32 Hz), 3.72 (1H, d, J=10.32 Hz), 3.44 (2H, s),3.18-3.26 (1H, m), 3.06-3.13 (1H, m), 2.69-2.96 (4H, m), 1.94-2.19 (2H,m), 1.45-1.86 (3H, m). MS (LC/MS) R.T.=0.76; [M+H]⁺=304.30.

Example 219(R)—N-(5-(Cyclopentyloxy)pyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 2-Chloro-5-(cyclopentyloxy)pyrimidine

A mixture of 2-chloropyrimidin-5-ol (1 g, 7.66 mmol), chlorocyclopentane(2.39 mL, 22.98 mmol) and potassium carbonate (3.18 g, 22.98 mmol) inN,N-dimethylformamide were heated at 65° C. for 16 h at ambienttemperature. Water was added and the mixture was extracted with ethylacetate. The organic layer was washed with water and brine, dried oversodium sulfate and concentrated in vacuo. The residue was purified bycolumn chromatography (0-25% ethyl acetate/hexanes) to afford2-chloro-5-(cyclopentyloxy)pyrimidine (831 mg, 4.18 mmol, 54.6% yield)as a white solid. MS (LC/MS) R.T.=2.32; [M+H]⁺=199.23.

Step B: 5-(Cyclopentyloxy)pyrimidin-2-amine

5-(Cyclopentyloxy)pyrimidin-2-amine was prepared from2-chloro-5-(cyclopentyloxy)pyrimidine by following the generalprocedures of Example 218, Step C. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.99(2H, s), 6.18 (2H, s), 4.54-4.75 (1H, m), 1.30-1.91 (8H, m). MS (LC/MS)R.T.=1.47; [M+H]⁺=180.24.

Step C.(R)—N-(5-(Cyclopentyloxy)pyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(5-(Cyclopentyloxy)pyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared from 5-(cyclopentyloxy)pyrimidin-2-amine by following thegeneral procedures of Example 23, Steps A-B. ¹H NMR (400 MHz, MeOD-d₄) δppm 8.24 (2H, s), 4.76-4.86 (1H, m), 3.98 (1H, d, J=10.07 Hz), 3.69 (1H,d, J=10.07 Hz), 3.33 (1H, d), 3.20 (1H, d), 2.77-3.08 (4H, m), 2.04-2.26(2H, m), 1.49-2.03 (11H, m). MS (LC/MS) R.T.=1.56; [M+H]⁺=344.32.

The compounds in Table 5 were synthesized according to the method ofExample 218 using the appropriate commercially available chlorides as inExample 218, Step C.

TABLE 4

Example LCMS LCMS Number R₁ RT (min) Ion [M + H]⁺ ¹H NMR 220

0.99 310.30 ¹H NMR (400 MHz, CDCl₃) δ ppm 9.82 (1 H, br. s.), 8.62 (1 H,s), 7.95 (1 H, dd, J = 8.18, 1.13 Hz), 7.72 (1 H, dd, J = 8.18, 1.13Hz), 7.58-7.64 (1 H, m, J = 7.62, 7.62, 7.05, 1.39 Hz), 7.51 (1 H, ddd,J = 7.68, 7.05, 1.26 Hz), 4.05 (1 H, d, J = 9.32 Hz), 3.70 (1 H, d, J =9.57 Hz), 3.39 (1 H, dd, J = 14.86, 1.51 Hz), 2.72-3.06 (5 H, m),2.12-2.26 (2 H, m), 1.69- 1.80 (1 H, m), 1.45-1.64 (2 H, m). M.P. 212-5°C. 221

1.32 180.09 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.31 (1 H, s), 7.80 (1 H, d,J = 2.52 Hz), 7.55 (1 H, dd, J = 8.81, 2.52 Hz), 7.50 (1 H, d, J = 9.06Hz), 7.13 (2 H, s) 222

0.90 316.30 ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.60 (s, 1 H), 7.60 (d, J =6.04 Hz, 1 H), 7.52 (s, 1 H), 4.04-4.17 (m, 1 H), 3.73-3.87 (m, 1 H),3.23-3.26 (m, 1 H), 3.07-3.19 (m, 1 H), 2.88-3.01 (m, 2 H), 2.75-2.88(m, 2 H), 2.08-2.27 (m, 2 H), 1.56-1.86 (m, 3 H) 223

2.28 358.20 ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.52 (1 H, s), 7.30 (1 H, d,J = 1.01 Hz), 4.03-4.09 (1 H, m), 3.76 (1 H, d, J = 10.07 Hz), 3.16-3.27(2 H, m), 3.06-3.14 (1 H, m), 2.68-3.01 (4 H, m), 2.01-2.23 (2 H, m),1.54-1.82 (3 H, m), 1.37 (6 H, d, J = 6.80 Hz) 224

0.86 302.24 ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.63 (1 H, s), 6.73 (1 H,br. s.), 4.02 (1 H, d, J = 10.32 Hz), 3.72 (1 H, d, J = 10.32 Hz),3.17-3.25(1 H, m), 3.01-3.13 (1 H, m), 2.68-2.97 (5 H, m), 1.98-2.16 (2H, m), 1.51-1.82 (3 H, m), 1.24 (6 H, d, J = 7.05 Hz) 225

0.25 274.19 ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.60 (1 H, s), 6.71 (1 H,br. s.), 4.02 (1 H, d, J = 10.32 Hz), 3.71 (1 H, d, J = 10.32 Hz),3.17-3.24 (1 H, m), 3.04-3.13 (1 H, m), 2.65-3.02 (4 H, m), 2.37 (3 H,s), 1.99-2.20 (2 H, m), 1.32-1.88 (3 H, m) 226

0.37 274.26 ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.38 (2 H, s), 3.97 (1 H, d,J = 10.07 Hz), 3.66 (1 H, d, J = 10.07 Hz), 3.16-3.25 (1 H, m),3.02-3.13 (1 H, m), 2.92 (2 H, t, J = 7.55 Hz), 2.73-2.86 (2 H, m), 2.21(3 H, s), 2.03-2.16 (2 H, m), 1.45-1.86 (3 H, m) 227

0.96 288.31 ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.41 (2 H, s), 3.98 (1 H, d,J = 10.07 Hz), 3.67 (1 H, d, J = 10.07 Hz), 3.17-3.25 (1 H, m),3.02-3.13 (1 H, m), 2.92 (2 H, t, J = 7.43 Hz), 2.72-2.87 (2 H, m), 2.57(2 H, q, J = 7.55 Hz), 2.01-2.23 (2 H, m), 1.48-1.84 (3 H, m), 1.22 (3H, t, J = 7.68 Hz)

Example 228(R)—N-(6-(2,2,2-Trifluoroethoxyl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 4-Chloro-6-(2,2,2-trifluoroethoxyl)pyrimidine

A solution of 2,2,2-trifluoroethanol (2.61 g, 26.10 mmol) intetrahydrofuran (12 ml) was added dropwise to a suspension of sodiumhydride (1.31 g, 32.60 mmol) in tetrahydrofuran (48 ml) at 0° C. Themixture was stirred at 0° C. for 30 min and a solution of4,6-dichloropyrimidine (3.6 g, 24.16 mmol) in tetrahydrofuran (12 ml)was added at 0° C. The reaction mixture was stirred at ambienttemperature for 3 h and poured into sat. aqueous ammonium chloride andextracted with ethyl acetate. The ethyl acetate extract was washed withwater, dried over magnesium sulfate and concentrated in vacuo. Theorange residue was purified by column chromatography (10-40% ethylacetate/hexanes) to afford 4-chloro-6-(2,2,2-trifluoroethoxyl)pyrimidine(2.0 g, 2.41 mmol, 38.9% yield) as a pale yellow oil. MS (LC/MS)R.T.=2.78; [M+H]⁺=213.12.

Step B: 6-(2,2,2-Trifluoroethoxyl)pyrimidin-4-amine

6-(2,2,2-trifluoroethoxyl)pyrimidin-4-amine was prepared from4-chloro-6-(2,2,2-trifluoroethoxyl)pyrimidine by following the generalprocedure of Example 218, Step C. MS (LC/MS) R.T.=1.16; [M+H]⁺=194.07.

Step C:(R)—N-(6-(2,2,2-Trifluoroethoxyl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(6-(2,2,2-trifluoroethoxyl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared from 6-(2,2,2-trifluoroethoxyl)pyrimidin-4-amine byfollowing the general procedures of Example 23, Steps A-B. ¹H NMR (400MHz, CDCl₃) δ ppm 9.30 (1H, br. s.), 8.39 (1H, s), 6.38 (1H, br. s.),4.59-4.84 (2H, m), 3.94 (1H, d, J=9.32 Hz), 3.59 (1H, d, J=9.57 Hz),3.33 (1H, d, J=16.62 Hz), 2.61-3.01 (5H, m), 1.97-2.25 (2H, m),1.37-1.81 (3H, m). MS (LC/MS) R.T.=1.42; [M+H]⁺=358.33.

Example 229(R)—N-(5-Bromo-4-isopropylpyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 4-Isopropylpyrimidin-2-amine

4-Isopropylpyrimidin-2-amine was prepared from2-chloro-4-isopropylpyrimidine by following the general procedure forExample 218, Step C.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.10 (1H, d, J=5.04 Hz), 6.45 (3H, d,J=5.04 Hz), 2.59-2.80 (1H, m), 1.15 (6H, d, J=7.05 Hz). MS (LC/MS)R.T.=0.76; [M+H]⁺=138.12.

Step B: 5-Bromo-4-isopropylpyrimidin-2-amine

N-Bromosuccinimide (0.5 g, 2.8 mmol) was added to a solution of4-isopropylpyrimidin-2-amine (0.39 g, 2.81 mmol) in chloroform. Theresultant yellow solution was stirred at ambient temperature for 1 h andconcentrated in vacuo. The residue was purified by column chromatography(3-10% 9:1 methanol:ammonium hydroxide in chloroform) to afford5-bromo-4-isopropylpyrimidin-2-amine (0.69 g, 3.18 mmol, 113%) as a paleyellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.21 (1H, s), 6.75 (2H,s), 3.10-3.23 (1H, m), 1.14 (6H, d, J=6.80 Hz). MS (LC/MS) R.T.=2.58;[M]⁺=216.09.

Step C:(R)—N-(5-Bromo-4-isopropylpyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(5-Bromo-4-isopropylpyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared from 5-bromo-4-isopropylpyrimidin-2-amine by following thegeneral procedures of Example 23, Steps A-B. ¹H NMR (400 MHz, MeOD-d₄) δppm 8.49 (1H, s), 4.02 (1H, d, J=10.07 Hz), 3.72 (1H, d, J=10.07 Hz),3.34-3.44 (1H, m), 3.23 (1H, s), 3.06-3.15 (1H, m), 2.95 (2H, t, J=7.55Hz), 2.75-2.89 (2H, m), 2.00-2.21 (2H, m), 1.52-1.83 (3H, m), 1.24 (6H,d, J=6.80 Hz). MS (LC/MS) R.T.=1.84; [M+H]⁺=382.24.

Example 230(R)—N-(5-Bromo-4-(pyridin-3-yl)pyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(5-Bromo-4-(pyridin-3-yl)pyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared from 4-(pyridin-3-yl)pyrimidin-2-amine by following thegeneral procedures of Example 229, Steps B-C. ¹H NMR (400 MHz, MeOD-d₄)δ ppm 8.92 (1H, d, J=1.51 Hz), 8.73 (1H, s), 8.64 (1H, dd, J=4.91, 1.64Hz), 8.23 (1H, dt, J=8.06, 1.89 Hz), 7.56 (1H, dd, J=7.93, 4.91 Hz),4.00 (1H, d, J=10.07 Hz), 3.69 (1H, d, J=10.07 Hz), 3.22 (1H, d), 3.07(1H, d), 2.60-2.99 (4H, m), 2.00-2.21 (2H, m), 1.50-1.83 (3H, m). MS(LC/MS) R.T.=0.76; [M+H]⁺=416.30.

Example 231(R)—N-(6-(Cyclopentyloxy)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 4-Chloro-6-(cyclopentyloxy)pyrimidine

A solution of cyclopentanol (2.25 g, 26.1 mmol) in tetrahydrofuran (12ml) was added dropwise to a suspension of sodium hydride (1.31 g, 32.6mmol) in tetrahydrofuran (48 ml) at 0° C. The mixture was stirred at 0°C. for 30 min and a solution of 4,6-dichloropyrimidine (3.6 g, 24.16mmol) in tetrahydrofuran (12 ml) was added at 0° C. The reaction mixturewas stirred at ambient temperature for 3 h and poured into sat. aqueousammonium chloride and extracted with ethyl acetate. The organic layerswere washed with water, dried over magnesium sulfate and concentrated invacuo. The orange residue was purified by column chromatography (10-40%ethyl acetate/hexanes). To afford 4-chloro-6-(cyclopentyloxy)pyrimidineas a pale yellow oil. This material was used directly for the nextreaction.

Step B: 6-(Cyclopentyloxy)pyrimidin-4-amine

6-(Cyclopentyloxy)pyrimidin-4-amine was prepared from4-chloro-6-(cyclopentyloxy)pyrimidine by following the general procedureof Example 218, Step C. MS (LC/MS) R.T.=1.64; [M+H]⁺=180.22.

Step C:(R)—N-(6-(Cyclopentyloxy)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(6-(cyclopentyloxy)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared from 6-(cyclopentyloxy)pyrimidin-4-amine by following thegeneral procedures of Example 23, Steps A-B. ¹H NMR (400 MHz, MeOD-d₄) δppm 8.37 (1H, s), 6.16 (1H, br. s.), 5.27 (1H, br. s.), 3.98 (1H, d,J=10.32 Hz), 3.67 (1H, d, J=10.32 Hz), 3.15-3.24 (1H, m), 3.02-3.12 (1H,m), 2.71-2.97 (4H, m), 2.01-2.14 (2H, m), 1.87-2.00 (3H, m), 1.49-1.84(8H, m). MS (LC/MS) R.T.=1.96; [M+H]⁺=344.34.

Example 232(R)—N-(6-Isopropoxypyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(6-Isopropoxypyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared from 4,6-dichloropyrimidine by following the generalprocedures of Example 231, Steps A-C. ¹H NMR (400 MHz, MeOD-d₄) δ ppm8.37 (1H, s), 6.13 (1H, br. s.), 5.09-5.30 (1H, m), 3.98 (1H, d, J=10.32Hz), 3.67 (1H, d, J=10.32 Hz), 3.13-3.24 (1H, m), 3.01-3.09 (1H, m),2.68-2.98 (4H, m), 1.98-2.17 (2H, m), 1.49-1.83 (3H, m), 1.30 (6H, d,J=6.04 Hz). MS (LC/MS) R.T.=1.36; [M+H]⁺=318.24.

Example 233(R)—N-(6-(2,2-Difluoroethoxyl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(6-(2,2-Difluoroethoxyl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared from 4,6-dichloropyrimidine by following the generalprocedures of Example 231, Steps A-C. M.P. 83-8° C. 1H NMR (400 MHz,MeOD-d₄) δ ppm 8.42 (1H, s), 5.93-6.37 (2H, m), 4.52 (2H, td, J=13.98,3.78 Hz), 3.99 (1H, d, J=10.32 Hz), 3.68 (1H, d, J=10.32 Hz), 3.19 (1H,d), 3.07 (1H, d), 2.67-2.97 (4H, m), 1.99-2.19 (2H, m), 1.51-1.82 (3H,m). MS (LC/MS) R.T.=0.99; [M+H]⁺=340.26.

Example 234(R)—N-(Pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(Pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared from(R)—N-(6-bromopyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(from Example 155) according to the general procedure of Example 19,Step C. ¹H NMR (500 MHz, MeOD-d₄) δ ppm 8.26 (d, J=4.88 Hz, 1H),7.58-7.74 (m, 1H), 6.85-7.02 (m, 2H), 4.00 (d, J=10.07 Hz, 1H), 3.70 (d,J=10.07 Hz, 1H), 3.26-3.35 (m, 1H), 3.14-3.21 (m, 1H), 3.02 (d, J=8.24Hz, 2H), 2.84-2.97 (m, 2H), 2.11-2.25 (m, 2H), 1.58-1.92 (m, 3H). MS(LC/MS) R.T.=0.30; [M+H]⁺=259.16.

Example 235(R)—N-(Pyridin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(Pyridin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared from(R)—N-(2-bromopyridin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(from Example 154) according to the procedure of Example 19, Step C. ¹HNMR (500 MHz, MeOD-d₄) δ ppm 8.31 (d, J=6.41 Hz, 2H), 7.39 (d, J=3.97Hz, 2H), 4.01 (d, J=12.21 Hz, 1H), 3.70 (d, J=11.90 Hz, 1H), 3.37 (s,1H), 3.29 (s, 1H), 3.18 (d, J=1.83 Hz, 1H), 3.15 (d, J=2.14 Hz, 1H),2.86-3.09 (m, 3H), 2.02-2.20 (m, 1H), 1.59-1.88 (m, 3H). MS (LC/MS)R.T.=0.22; [M+H]⁺=259.16.

Example 236(R)—N-(5-(Benzyloxy)thiazolo[5,4-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 5-(Benzyloxy)thiazolo[5,4-b]pyridin-2-amine

Potassium thiocyanate (12.42 g, 128 mmol) was suspended in acetic acid(45.0 mL) and cooled to 0° C. 6-(Benzyloxy)pyridin-3-amine (3.2 g, 15.98mmol), prepared according to WO2006/044707 was added. Bromine (2.55 mL,49.5 mmol) in acetic acid (15 mL) was added dropwise over 30 minutesduring which time the reaction mixture became very thick. It was allowedto warm to room temperature slowly and stirred overnight.

Water (20 ml) was added and the reaction mixture was heated to 90° C.and filtered hot. The filtrate was saved and the filter cake returned tothe reaction flask, to which was added an additional 40 ml HOAc. Themixture was again heated to 90° C. and filtered hot. The combinedfiltrates were cooled on ice bath and NH₄OH was added dropwise untilpH>8. A yellow precipitate formed which was collected by filtration. Thesolids were dried in vacuo for 1 h to provide5-(benzyloxy)thiazolo[5,4-b]pyridin-2-amine (1.95 g, 7.58 mmol, 47.4%yield), which was used without further purification. 1H NMR (400 MHz,CDCl₃) δ ppm 7.70 (d, J=8.78 Hz, 1H) 7.48 (d, J=7.28 Hz, 2H) 7.39 (t,J=7.28 Hz, 2H) 7.30-7.36 (m, 1H) 6.78 (d, J=8.78 Hz, 1H) 5.39 (s, 2H)5.14 (br. s., 2H).

Step B: Dimethyl5-(benzyloxy)thiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate

To a suspension of 5-(benzyloxy)thiazolo[5,4-b]pyridin-2-amine (800 mg,3.11 mmol) in DMF (3.1 mL) was added 20.0M sodium hydroxide (0.3 mL,6.22 mmol). The mixture was allowed to stir 10 min at room temperatureat which time carbon disulfide was added (0.47 mL, 7.77 mmol) and themixture was stirred for 10 minutes. An additional portion of 20.0Msodium hydroxide (0.3 mL, 6.22 mmol) was added and the mixture was againstirred for 10 minutes. Finally, iodomethane (0.47 mL, 7.46 mmol) wasadded dropwise. The mixture was stirred for 1 hour, at which time it waspoured into water and extracted with EtOAc (3×). The combined organicswere washed with brine, dried over sodium sulfate, filtered andconcentrated in vacuo. The crude mixture was purified by silica gelchromatography (2-20% EtOAc/CHCl₃) to provide dimethyl5-(benzyloxy)thiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate (1.02 g,91% yield) as a yellow crystalline solid. 1H NMR (400 MHz, CDCl₃) δ ppm8.02 (d, J=8.78 Hz, 1H) 7.51 (d, J=7.28 Hz, 2H) 7.38-7.45 (m, 2H)7.32-7.38 (m, 1H) 6.89 (d, J=8.53 Hz, 1H) 5.46 (s, 2H) 2.65 (s, 6H).

Step C:(R)—N-(5-(benzyloxy)thiazolo[5,4-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

A mixture of dimethyl5-(benzyloxy)thiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate (500 mg,1.38 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (317 mg,1.38 mmol) and cesium carbonate (1.0 g, 3.07 mmol) in DMF (7 mL) washeated to 100° C. for 2 hours. The reaction mixture was cooled toambient temperature, poured into water and extracted with chloroform(4×). The combined organics were washed with brine, dried over sodiumsulfate, filtered and concentrated in vacuo. The mixture was purified bysilica gel chromatography (2-20% [9:1 methanol:ammoniumhydroxide]-chloroform) to afford(R)—N-(5-(benzyloxy)thiazolo[5,4-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(390 mg, 67% yield). 1H NMR (500 MHz, CDCl₃) δ ppm 9.18 (br. s., 1H)7.76 (d, J=8.85 Hz, 1H) 7.50 (d, J=7.32 Hz, 2H) 7.41 (t, J=7.32 Hz, 2H)7.32-7.37 (m, 1H) 5.42 (s, 2H) 4.02 (d, J=9.46 Hz, 1H) 3.68 (d, J=9.46Hz, 1H) 3.37-3.44 (m, 1H) 2.75-3.06 (m, 5H) 2.13-2.25 (m, 2H) 1.73-1.82(m, 1H) 1.49-1.70 (m, 3H). MS (LC/MS) R.T.=1.69; [M+H]⁺=421.98.

Example 237(R)-2-(4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]-2-ylamino)thiazolo[5,4-b]pyridin-5(4H)-one

(R)—N-(5-(benzyloxy)thiazolo[5,4-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(390 mg, 0.925 mmol) was dissolved in TFA and allowed to react for 4hours at ambient temperature, at which time LCMS and TLC showed thestarting material to be mostly consumed. The TFA was removed in vacuoand the crude mixture was purified by preparative HPLC. The combinedproduct fractions were concentrated in vacuo and triturated with etherto afford(R)-2-(4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]-2-ylamino)thiazolo[5,4-b]pyridin-5(4H)-one,TFA (164 mg, 0.368 mmol, 39.8% yield). M.P. 245 (dec). 1H NMR (400 MHz,DMSO-d₆) δ ppm 9.99 (br. s., 1H) 9.05 (br. s., 1H) 7.81 (d, J=8.53 Hz,1H) 6.65 (d, J=8.78 Hz, 1H) 3.96 (d, J=10.29 Hz, 1H) 3.82 (d, J=10.54Hz, 1H) 3.63-3.78 (m, 2H) 3.36-3.47 (m, 1H) 3.16-3.34 (m, 3H) 2.43 (br.s., 1H) 2.16 (br. s., 1H) 1.76-2.07 (m, 3H). MS (LC/MS) R.T.=0.50;[M+H]⁺=332.15.

Example 238(R)—N-(6-(3-Methoxyphenyl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 6-(3-Methoxyphenyl)pyrimidin-4-amine

A mixture of 6-chloropyrimidin-4-amine (0.324 g, 2.5 mmol),3-methoxyphenylboronic acid (0.475 g, 3.13 mmol), Na₂CO₃ (0.795 g, 7.50mmol) and bis(triphenylphosphine)palladium(II) chloride (0.035 g, 0.050mmol) was suspended in DME/EtOH/water (15:2:3 mL), heated in themicrowave synthesizer at 125° C. for 20 min and concentrated. Theresidue was purified by silica gel chromatography (10-60% ethylacetate-hexanes) to afford 6-(3-methoxyphenyl)pyrimidin-4-amine (0.35 g,1.74 mmol, 70% yield) as an off-white solid. LCMS R.T.=1.28;[M+H]⁺=201.98.

Step B: 4-Isothiocyanato-6-(3-methoxyphenyl)pyrimidine

To a solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (0.970 g, 4.17mmol) in dichloromethane at room temperature was added6-(3-methoxyphenyl)pyrimidin-4-amine (0.7 g, 3.48 mmol). The reactionwas stirred at room temperature for 18 hours. The LC/MS showed thedesired product peak as a major peak. The deep orange solution wasconcentrated and the remaining residue was filtered. The filtrate waspurified by silica gel chromatography (0-10% ethyl acetate-hexanes) toafford 4-isothiocyanato-6-(3-methoxyphenyl)pyrimidine (0.39 g, 4.31mmol, 46% yield) as a yellow oil. LCMS R.T.=2.91; [M+H]⁺=244.03.

Step C:R)—N-(6-(3-Methoxyphenyl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.363 g, 1.583mmol) in N,N-dimethylformamide (20 mL) was added Cs₂CO₃ (1.289 g, 3.96mmol) and 4-isothiocyanato-6-(3-methoxyphenyl)pyrimidine. The suspensionwas stirred at room temperature for 30 minutes.N,N′-diisopropylcarbodiimide (0.740 mL, 4.75 mmol) was then added andthe mixture was continued to stir at room temperature for 18 hours. Themixture was concentrated and purified by silica gel chromatography(5-25% 9:1 methanol:ammonium hydroxide-ethyl acetate) to afford(R)—N-(6-methoxypyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.294 g, 0.788 mmol, 50% yield) as a pale yellow solid. M.P 80-5° C. ¹HNMR (400 MHz, MeOD) δ ppm 8.77 (1H, s), 7.47-7.58 (2H, m), 7.39 (1H, t),7.20 (1H, br. s.), 7.04 (1H, dd), 4.05 (1H, d), 3.85 (3H, s), 3.74 (1H,d), 3.23 (1H, d), 3.10 (1H, d), 2.71-3.00 (4H, m), 2.03-2.22 (2H, m),1.53-1.85 (3H, m). MS (LC/MS) R.T.=1.58; [M+H]⁺=366.15.

Example 239

(R)—N-(Isoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 3-Isothiocyanatoisoquinoline

To a solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (0.805 g, 3.47mmol) in dichloromethane at room temperature was addedisoquinolin-3-amine (0.5 g, 3.47 mmol). The reaction was stirred at roomtemperature for 18 hours. The LC/MS showed the desired product peak amajor peak. The deep orange solution was concentrated and filtered. Thefiltrate was purified by silica gel chromatography (0-40% ethylacetate-hexanes) to afford4-isothiocyanato-6-(3-methoxyphenyl)pyrimidine (0.55 g, 2.96 mmol, 85%yield) a white solid. LCMS R.T.=2.47; [M+H]⁺=187.23.

Step B:(R)—N-(Isoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.2 g, 0.873mmol) in N,N-dimethylformamide (20 mL) was added Cs₂CO₃ (0.711 g, 2.182mmol) and 3-isothiocyanatoisoquinoline (0.163 g, 0.873 mmol). Thesuspension was stirred at room temperature for 30 minutes.N,N′-Diisopropylcarbodiimide (0.408 mL, 2.62 mmol) was then added andthe mixture was stirred at room temperature for 18 hours. The mixturewas concentrated and purified by silica gel chromatography (5-25% [9:1methanol:ammonium hydroxide]-ethyl acetate) to afford(R)—N-(isoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.16 g, 0.508 mmol, 58% yield) as an off-white solid. M.P. 196-200° C.¹H NMR (400 MHz, MeOD) δ ppm 9.00 (1H, s), 7.92 (1H, d), 7.71 (1H, d),7.59 (1H, t), 7.20-7.45 (2H, m), 3.96 (1H, d), 3.65 (1H, d), 3.22 (1H,d), 3.08 (1H, d), 2.66-3.00 (4H, m), 2.05-2.23 (2H, m), 1.50-1.86 (3H,m). R.T.=1.37; [M+H]⁺=309.31.

Example 240(R)—N-(6-Phenoxypyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 6-Phenoxypyrimidin-4-amine

6-Chloropyrimidin-4-amine (3.00 g, 23.14 mmol) was added to a solutionof sodium (0.197 g, 8.57 mmol) in phenol (11.29 g, 120 mmol) at 55° C.The mixture was heated at 140° C. for 2 h, then held at room temperaturefor 20 h. The reaction mixture was poured into 32% aqueous NaOH onice/water keeping the mixture temperature below 20° C. The mixture wasextracted with chloroform and the organic extract dried over calciumchloride and concentrated. The residue was purified by silica gelchromatography (2-20% ethyl acetate in hexanes) to afford6-phenoxypyrimidin-4-amine (0.6 g, 3.21 mmol, 75% yield) as a whitesolid. LCMS R.T.=1.37; [M+H]⁺=197.95.

Step B: 4-Isothiocyanato-6-phenoxypyrimidine

A mixture of 6-phenoxypyrimidin-4-amine (0.288 g, 1.538 mmol) and1,1′-thiocarbonyldipyridin-2(1H)-one (0.357 g, 1.538 mmol) in DCM wasstirred at rt for 18 h. The pale orange mixture was purified by silicagel chromatography (5-35% ethyl acetate-hexanes) to afford4-isothiocyanato-6-phenoxypyrimidine (0.55 g, 2.96 mmol, 85% yield) ayellow oil. LCMS R.T.=2.78; [M+H]⁺=229.94.

Step C:(R)—N-(6-Phenoxypyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.170 g, 0.742mmol) in N,N-dimethylformamide (20 mL) was added Cs₂CO₃ (0.604 g, 1.854mmol) and 4-isothiocyanato-6-phenoxypyrimidine (0.17 g, 0.742 mmol). Thesuspension was stirred at room temperature for 30 minutes.N,N′-diisopropylcarbodiimide (0.347 mL, 2.225 mmol) was then added andthe mixture was continued to stir at room temperature for 18 hours. Themixture was concentrated and purified by silica gel chromatography(5-25% 9:1 methanol:ammonium hydroxide-ethyl acetate) to afford(R)—N-(6-phenoxypyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.21 g, 0.72 mmol, 48.2% yield) as a pale yellow solid. ¹H NMR (500MHz, MeOD) δ ppm 8.43 (1H, s), 7.47 (2H, t), 7.30 (1H, t), 7.16 (2H, d),6.21 (1H, br. s.), 4.03 (1H, d), 3.72 (1H, d), 3.22 (1H, d), 3.11 (1H,d), 2.73-2.99 (4H, m), 2.00-2.18 (2H, m), 1.54-1.88 (3H, m). LCMSR.T.=1.46; [M+H]⁺=352.19.

Example 241(R)—N-(7-methoxyquinoxalin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: N-(2,4-Dimethoxybenzyl)-7-methoxyquinoxalin-2-amine

2-Chloro-7-methoxyquinoxaline (0.51 g, 2.62 mmol), prepared according toJ. Chem. Soc. Perk Trans. 1, 2001, 978-984, and(2,4-dimethoxyphenyl)methanamine (1.181 mL, 7.86 mmol) were microwavedin DMSO (2.5 mL) for 30 min at 150° C. This was diluted into 150 mLEtOAc and extracted three times with 100 mL brine. The crude product waspurified by flash chromatography on a 90 g silica gel cartridge with 20to 80% EtOAc in hexane, 50 min, at 40 mL/min to affordN-(2,4-dimethoxybenzyl)-7-methoxyquinoxalin-2-amine (795 mg, 2.443 mmol,93% yield).

1H NMR (400 MHz, CDCl₃) δ ppm 8.00 (1H, s), 7.70 (1H, d, J=8.81 Hz),7.29 (1H, d, J=8.31 Hz), 7.05 (1H, d, J=2.77 Hz), 6.97 (1H, dd, J=9.06,2.77 Hz), 6.47 (1H, d, J=2.27 Hz), 6.43 (1H, dd, J=8.18, 2.39 Hz), 5.22(1H, t, J=5.29 Hz), 4.63 (2H, d, J=5.54 Hz), 3.91 (3H, s), 3.83 (3H, s),3.78 (3H, s)

LCMS: RT=1.91 min, MH+=326.15.

Step B: 7-Methoxyquinoxalin-2-amine 2,2,2-trifluoroacetate

N-(2,4-Dimethoxybenzyl)-7-methoxyquinoxalin-2-amine (0.79 g, 2.428 mmol)was stirred in TFA (10 mL, 130 mmol)/CH₂Cl₂ (10 mL) at room temperaturefor 30 min. Solvents were removed on the rotary evaporator. Saturatedaqueous NaHCO₃ (200 mL) was added to the red residue, which precipitateda yellow solid. The mixture was extracted extensively with DCM. Theorganic layer was concentrated and dried under vacuum to yield7-methoxyquinoxalin-2-amine 2,2,2-trifluoroacetate (0.70 g, 2.4 mmol,99% yield).

1H NMR (400 MHz, DMSO-d₆) δ ppm 8.10 (1H, s), 7.63 (1H, d, J=9.07 Hz),6.95 (1H, dd, J=9.06, 2.77 Hz), 6.89 (1H, d, J=2.77 Hz), 6.85 (2H, br.s.), 3.84 (3H, s)

LCMS: RT=1.04 min, MH+=176.14.

Step C: 2-Isothiocyanato-7-methoxyquinoxaline

A mixture of 7-methoxyquinoxalin-2-amine 2,2,2-trifluoroacetate (578 mg,2 mmol), triethylamine (335 μL, 2.400 mmol), and1,1′-thiocarbonyldipyridin-2(1H)-one (557 mg, 2.400 mmol) was stirred in5 mL DCM for 24 h. The reaction was directly eluted on a 120 g silicagel cartridge with 0 to 25% EtOAc in hexane, 25 min, at 35 mL/min toafford 2-isothiocyanato-7-methoxyquinoxaline (84 mg, 0.387 mmol, 19%yield).

LCMS: RT=2.49 min, MH+=218.06.

Step D:(R)—N-(7-Methoxyquinoxalin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(7-Methoxyquinoxalin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas synthesized by the method of Example 23, Step B. Flashchromatography on a 120 g silica gel cartridge with 1-4% [9:1MeOH/NH4OH] in CHCl3, 50 min, afforded 24 mg (17% yield).

1H NMR (400 MHz, CDCl₃) δ ppm 9.73 (1H, br. s.), 8.45 (1H, s), 7.80 (1H,d, J=9.07 Hz), 7.12 (1H, dd, J=9.06, 2.77 Hz), 7.03 (1H, d, J=2.52 Hz),4.02 (1H, d, J=9.32 Hz), 3.90 (3H, s), 3.67 (1H, d, J=9.32 Hz), 3.36(1H, dd, J=14.86, 1.51 Hz), 2.69-3.06 (5H, m), 2.10-2.26 (2H, m),1.66-1.80 (1H, m), 1.43-1.63 (2H, m)

LCMS: RT=0.835 min, MH−=338.2, MH+=340.1.

Example 242(R)—N-(6-Methylquinoxalin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: N-(2,4-Dimethoxybenzyl)-6-methylquinoxalin-2-amine

2-Chloro-6-methylquinoxaline (0.51 g, 2.86 mmol), prepared according toJ. Chem. Soc. 1948, 1310-1313, and (2,4-dimethoxyphenyl)methanamine(1.29 mL, 8.57 mmol) were microwaved in DMSO (2.5 mL) for 30 min at 150°C. This was diluted into 150 mL EtOAc and extracted three times with 100mL brine. The crude product was purified by flash chromatography on a 90g silica gel cartridge with 20 to 60% EtOAc in hexane, 50 min, at 40mL/min to afford N-(2,4-dimethoxybenzyl)-6-methylquinoxalin-2-amine (848mg, 2.74 mmol, 96% yield).

1H NMR (400 MHz, CDCl₃) δ ppm 8.12 (1H, s), 7.60 (1H, s), 7.59 (1H, d,J=5.79 Hz), 7.38 (1H, dd, J=8.56, 1.76 Hz), 7.30 (1H, d, J=8.31 Hz),6.46 (1H, d, J=2.27 Hz), 6.42 (1H, dd, J=8.18, 2.39 Hz), 5.20 (1H, t,J=5.41 Hz), 4.62 (2H, d, J=5.54 Hz), 3.83 (3H, s), 3.77 (3H, s), 2.46(3H, s)

LCMS: RT=1.93 min, MH+=310.20.

Step B: 6-Methylquinoxalin-2-amine 2,2,2-trifluoroacetate

N-(2,4-Dimethoxybenzyl)-6-methylquinoxalin-2-amine (0.84 g, 2.72 mmol)was stirred in TFA (10 mL, 130 mmol)/CH₂Cl₂ (10 mL) at room temperaturefor 30 min. Solvents were removed on the rotary evaporator. Saturatedaqueous Na₂CO₃ (200 mL) was added to the red residue, which thenprecipitated a tan solid. The mixture was extracted extensively withDCM. The organic layer was dried over sodium sulfate, concentrated, anddried under vacuum to afford 6-methylquinoxalin-2-amine2,2,2-trifluoroacetate (640 mg, 2.343 mmol, 86% yield).

1H NMR (400 MHz, DMSO-d₆) δ ppm 8.24 (1H, s), 7.55 (1H, s), 7.34-7.45(2H, m), 6.82 (2H, s), 2.41 (3H, s)

LCMS: RT=1.07 min, MH+=160.12.

Step C: 2-Isothiocyanato-6-methylquinoxaline

A mixture of 6-methylquinoxalin-2-amine 2,2,2-trifluoroacetate (546 mg,2 mmol), triethylamine (243 mg, 2.400 mmol), and1,1′-thiocarbonyldipyridin-2(1H)-one (557 mg, 2.40 mmol) was stirred in5 mL DCM for 4 h. The reaction was directly eluted on a 120 g silica gelcartridge with 0 to 25% EtOAc in hexane, 25 min, at 35 mL/min to afford2-isothiocyanato-6-methylquinoxaline (153 mg, 0.760 mmol, 38% yield).

LCMS: RT=2.59 min, MH+=202.04

Step D:(R)—N-(6-Methylquinoxalin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(6-Methylquinoxalin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas synthesized by the method of Example 23, Step B. Flashchromatography on a 120 g silica gel cartridge with 1 to 4% [9:1MeOH/NH₄OH] in CHCl₃, 50 min, afforded 46 mg (19% yield).

1H NMR (400 MHz, CDCl₃) δ ppm 9.75 (1H, br. s.), 8.57 (1H, s), 7.71 (1H,s), 7.60 (1H, d, J=8.56 Hz), 7.42 (1H, dd, J=8.44, 1.89 Hz), 4.01 (1H,d, J=9.57 Hz), 3.68 (1H, d, J=9.32 Hz), 3.38 (1H, dd, J=14.86, 1.01 Hz),2.73-3.08 (5H, m), 2.50 (3H, s), 2.16-2.26 (1H, m), 2.14 (1H, br. s.),1.67-1.79 (1H, m), 1.45-1.65 (2H, m).

LCMS: RT=0.838 min, MH−=322.2, MH+=324.2.

Example 243(R)—N-(7-Methylquinoxalin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: N-(2,4-Dimethoxybenzyl)-7-methylquinoxalin-2-amine

2-Chloro-7-methylquinoxaline (0.51 g, 2.86 mmol),), prepared accordingto J. Chem. Soc. 1948 1310-1313, and (2,4-dimethoxyphenyl)methanamine(1.29 mL, 8.57 mmol) were microwaved in DMSO (2.5 mL) for 30 min at 150°C. This was diluted into 150 mL EtOAc and extracted three times with 100mL brine. The crude product was purified by flash chromatography on a 90g silica gel cartridge with 20 to 80% EtOAc in hexane, 50 min, at 40mL/min to afford N-(2,4-dimethoxybenzyl)-7-methylquinoxalin-2-amine (860mg, 2.78 mmol, 97% yield).

1H NMR (400 MHz, CDCl₃) δ ppm 8.08 (1H, s), 7.70 (1H, d, J=8.31 Hz),7.49 (1H, s), 7.30 (1H, d, J=8.06 Hz), 7.17 (1H, dd, J=8.31, 2.01 Hz),6.47 (1H, d, J=2.52 Hz), 6.42 (1H, dd, J=8.31, 2.52 Hz), 5.23 (1H, t,J=5.16 Hz), 4.63 (2H, d, J=5.79 Hz), 3.83 (3H, s), 3.78 (3H, s), 2.48(3H, s).

LCMS: RT=1.93 min, MH+=310.20.

Step B: 7-Methylquinoxalin-2-amine 2,2,2-trifluoroacetate

N-(2,4-Dimethoxybenzyl)-7-methylquinoxalin-2-amine (0.85 g, 2.75 mmol)was stirred in TFA (10 mL, 130 mmol)/CH2Cl2 (10 mL) at room temperaturefor 30 min. Solvents were removed on the rotary evaporator. Saturatedaqueous NaHCO₃ (200 mL) was added to the red residue, which thenprecipitated a pink solid. The mixture was extracted extensively withDCM. The organic layer was dried over sodium sulfate, concentrated, anddried under vacuum to afford 7-methylquinoxalin-2-amine2,2,2-trifluoroacetate (640 mg, 2.34 mmol, 85% yield).

1H NMR (400 MHz, DMSO-d₆) δ ppm 8.20 (1H, s), 7.64 (1H, d, J=8.31 Hz),7.28 (1H, s), 7.15 (1H, dd, J=8.31, 1.76 Hz), 6.89 (2H, s), 2.42 (3H,s).

LCMS: RT=1.07 min, MH+=160.12.

Step C: 2-Isothiocyanato-6-methylquinoxaline

A mixture of 7-methylquinoxalin-2-amine 2,2,2-trifluoroacetate (546 mg,2 mmol) 78263-058-01, triethylamine (243 mg, 2.40 mmol), and1,1′-thiocarbonyldipyridin-2(1H)-one (557 mg, 2.40 mmol) was stirred in5 mL DCM for 2 h. The reaction was directly eluted on a 120 g silica gelcartridge with 0 to 25% EtOAc in hexane, 25 min, at 35 mL/min to afford2-isothiocyanato-7-methylquinoxaline (185 mg, 0.919 mmol, 46% yield).

LCMS: RT=2.58 min, MH+=202.04

Step D:(R)—N-(7-Methylquinoxalin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(7-Methylquinoxalin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas synthesized by the method of Example 23, Step B. Flashchromatography on a 120 g silica gel cartridge with 1 to 3% [9:1MeOH/NH4OH] in CHCl3, 50 min, afforded 22 mg (7% yield).

1H NMR (400 MHz, CDCl₃) δ ppm 9.80 (1H, br. s.), 8.53 (1H, s), 7.81 (1H,d, J=8.31 Hz), 7.50 (1H, s), 7.31 (1H, dd, J=8.56, 1.76 Hz), 4.01 (1H,d, J=9.57 Hz), 3.66 (1H, d, J=9.32 Hz), 3.36 (1H, d, J=14.86 Hz),2.70-3.04 (5H, m), 2.50 (3H, s), 2.15-2.24 (1H, m), 2.13 (1H, br. s.),1.66-1.79 (1H, m), 1.44-1.63 (2H, m)

LCMS: RT=8.67 min, MH−=322.6, MH+=324.1.

Example 244(R)—N-(6-(Pyridin-3-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 6-(Pyridin-3-yl)pyrimidin-4-amine

A mixture of 6-chloropyrimidin-4-amine (0.324 g, 2.5 mmol),pyridin-3-ylboronic acid (0.384 g, 3.13 mmol), Na₂CO₃ (0.795 g, 7.50mmol) and bis(triphenylphosphine)palladium(II) chloride (0.035 g, 0.050mmol) was suspended in a mixture of DME/EtOH/water. The mixture washeated in the microwave synthesizer at 125° C. for 20 min andconcentrated. The residue was purified by silica gel chromatography(10-60% ethyl acetate in hexanes, then 5-25% 9:1 methanol:ammoniumhydroxide-ethyl acetate) to afford 6-(pyridin-3-yl)pyrimidin-4-amine(0.17 g, 0.987 mmol, 40% yield) as an off-white solid. LCMS R.T.=0.31;[M+H]⁺=173.11.

Step B: 4-Isothiocyanato-6-(pyridin-3-yl)pyrimidine

To a solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (0.682 g, 2.94mmol) in dichloromethane/N,N-dimethylformamide at room temperature wasadded 6-(pyridin-3-yl)pyrimidin-4-amine (0.337 g, 1.957 mmol). Themixture was heated at 60° C. for 18 hours. LC/MS showed the desiredproduct peak as the major peak. The deep orange mixture was purified bysilica gel chromatography (1-40% ethyl acetate-hexanes) to afford4-isothiocyanato-6-methoxypyrimidine (0.12 g, 0.56 mmol, 28.6% yield) asan orange oil.

Step C:(R)—N-(6-(Pyridin-3-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.13 g, 0.560mmol) in N,N-dimethylformamide (20 mL) was added Cs₂CO₃ (0.46 g, 1.4mmol) and 4-isothiocyanato-6-(pyridin-3-yl)pyrimidine (0.12 g, 0.56mmol). The suspension was stirred at room temperature for 30 minutes.N,N′-Diisopropylcarbodiimide (0.26 mL, 1.7 mmol) was then added and themixture was stirred at room temperature for 18 hours. The mixture wasconcentrated and purified by silica gel chromatography (0-10% [9:1methanol:ammonium hydroxide]-ethyl acetate) to afford(S)—N-(5-chloropyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.182 g, 0.613 mmol, 35% yield) as an off-white solid. ¹H NMR (400 MHz,MeOD) δ ppm 9.13-9.21 (1H, m), 8.82 (1H, d), 8.63 (1H, dd), 8.44 (1H,dt), 7.56 (1H, dd), 7.31 (1H, s), 4.06 (1H, d), 3.76 (1H, d), 3.20-3.28(1H, m), 3.08-3.16 (1H, m), 2.72-3.01 (4H, m), 2.00-2.24 (2H, m),1.52-1.83 (3H, m). LCMS R.T.=0.72; [M+H]⁺=337.2.

Example 245(R)—N-(2′-Methoxy-4,5′-bipyrimidin-6-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 2′-Methoxy-4,5′-bipyrimidin-6-amine

6-Chloropyrimidin-4-amine (0.35 g, 2.70 mmol),2-methoxypyrimidin-5-ylboronic acid (0.520 g, 3.38 mmol), Na₂CO₃ (0.859g, 8.11 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.038g, 0.054 mmol) were suspended in a mixture of DME/EtOH/water. (15:2:3mL). The mixture was heated in the microwave synthesizer at 125° C. for20 min and concentrated. The residue was purified by silica gelchromatography (0-5% 9:1 methanol:ammonium hydroxide-ethyl acetate) toafford 6-(pyridin-3-yl)pyrimidin-4-amine (0.28 g, 1.378 mmol, 51% yield)as an off-white solid. LCMS R.T.=0.53; [M+H]⁺=204.11.

Step B: 6-Isothiocyanato-2′-methoxy-4,5′-bipyrimidine

To a solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (0.832 g, 3.58mmol) in dichloromethane/N,N-dimethylformamide at room temperature wasadded 2′-methoxy-4,5′-bipyrimidin-6-amine (0.56 g, 2.76 mmol). Theorange mixture was heated at 60° C. for 18 hours. The LC/MS showed thedesired product peak as the major peak. The deep orange mixture waspurified by silica gel chromatography (0-40% ethyl acetate-hexanes) toafford 4-isothiocyanato-6-methoxypyrimidine (0.1 g, 0.408 mmol, 15%yield) as an orange solid. LCMS R.T.=2.29; [M+H]⁺=246.03.

Step C:(R)—N-(2′-Methoxy-4,5′-bipyrimidin-6-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.093 g, 0.41mmol) in N,N-dimethylformamide (20 mL) was added Cs₂CO₃ (0.33 g, 1mmol)) and 6-isothiocyanato-2′-methoxy-4,5′-bipyrimidine (0.1 g, 0.41mmol). The suspension was stirred at room temperature for 30 minutes.N,N′-Diisopropylcarbodiimide (0.19 mL, 1.2 mmol) was then added and themixture was stirred at room temperature for 18 hours. The mixture wasconcentrated and purified by silica gel chromatography (5-25% [9:1methanol:ammonium hydroxide]-ethyl acetate) to afford(R)—N-(2′-methoxy-4,5′-bipyrimidin-6-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.072 g, 0.188 mmol, 46% yield) as an off-white solid. ¹H NMR (400 MHz,MeOD) δ ppm 9.19 (2H, s), 8.80 (1H, d), 7.24 (1H, br. s.), 4.00-4.09(4H, m), 3.76 (1H, d), 3.23 (1H, s), 3.08-3.15 (1H, m), 2.72-3.04 (4H,m), 1.97-2.22 (2H, m), 1.38-1.85 (3H, m). R.T.=1.22; [M+H]⁺=368.22.

Example 246(R)—N-(6-(Pyridin-4-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 6-(Pyridin-4-yl)pyrimidin-4-amine

6-Chloropyrimidin-4-amine (0.324 g, 2.5 mmol), pyridin-4-ylboronic acid(0.384 g, 3.13 mmol), Na₂CO₃ (0.795 g, 7.50 mmol) andbis(triphenylphosphine)palladium(II) chloride (0.035 g, 0.050 mmol) weresuspended in a mixture of DME/EtOH/water (15:2:3 mL). The mixture washeated in the microwave synthesizer at 125° C. for 20 min andconcentrated. The residue was purified by silica gel chromatography(5-25% [9:1 methanol:ammonium hydroxide]-ethyl acetate) to afford6-(pyridin-3-yl)pyrimidin-4-amine (0.15 g, 0.871 mmol, 35% yield) as anoff-white solid. LCMS R.T.=0.30; [M+H]⁺=173.11.

Step B: 4-Isothiocyanato-6-(pyridin-4-yl)pyrimidine

To a solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (0.601 g, 2.59mmol) in dichloromethane/N,N-dimethylformamide at room temperature wasadded 6-(pyridin-4-yl)pyrimidin-4-amine (0.297 g, 1.725 mmol). Theorange mixture was heated at 60° C. for 18 hours. LC/MS showed thedesired product peak as the major peak. The deep orange mixture waspurified by silica gel chromatography (0-40% ethyl acetate-hexanes) toafford 4-isothiocyanato-6-(pyridin-4-yl)pyrimidine (0.055 g, 0.257 mmol,15% yield) as an orange solid. LCMS R.T.=1.46; [M+H]⁺=215.09.

Step C:(R)—N-(6-(Pyridin-4-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.059 g, 0.257mmol) in N,N-dimethylformamide (15 mL) was added Cs₂CO₃ (0.209 g, 0.642mmol) and 4-isothiocyanato-6-(pyridin-4-yl)pyrimidine (0.055 g, 0.257mmol). The suspension was stirred at room temperature for 30 minutes.N,N′-diisopropylcarbodiimide (0.12 mL, 0.77 mmol) was then added and themixture was continued to stir at room temperature for 18 hours. Themixture was concentrated and purified by silica gel chromatography(0-10% [9:1 methanol:ammonium hydroxide]-ethyl acetate) to afford(R)—N-(6-(pyridin-4-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.014 g, 0.04 mmol, 16% yield) as a yellow film. ¹H NMR (400 MHz, MeOD)δ ppm 8.85 (1H, d), 8.67 (2H, dd), 8.04 (2H, dd), 7.34 (1H, br. s.),4.06 (1H, d), 3.76 (1H, d), 3.23 (1H, d), 3.10 (1H, d), 2.70-2.99 (4H,m), 2.01-2.22 (2H, m), 1.53-1.86 (3H, m). LCMS R.T.=0.42; [M+H]⁺=337.14.

Example 247(R)-6-(4H-1′-Azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]-2-ylamino)-2-methylnicotinonitrile

Step A: 6-Isothiocyanato-2-methylnicotinonitrile

To 6-amino-2-methylnicotinonitrile (0.41 g, 3.08 mmol) indichloromethane (20 mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one(0.75 g, 3.23 mmol). The reaction was stirred at 40° C. for 3 hours. Thereaction was cooled to room temperature. The crude was purified bychromatography (Biotage: 25-100% ethyl acetate/hexane) to yield6-isothiocyanato-2-methylnicotinonitrile (0.52 g, 2.97 mmol, 96% yield).1H NMR (500 MHz, DMSO-D6) δ ppm 8.36 (d, J=8.24 Hz, 1H), 7.39 (d, J=8.24Hz, 1H), 2.65 (s, 3H). MS (LC/MS) R.T.=2.09; [M+H]⁺=176.0.

Step B:(R)-6-(4H-1′-Azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]-2-ylamino)-2-methylnicotinonitrile

To 6-isothiocyanato-2-methylnicotinonitrile (0.25 g, 1.43 mmol) inN,N-dimethylformamide (20 mL) was added triethylamine (0.5 mL, 3.666mmol) and 3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.33 g, 1.46mmol) at room temperature. The reaction was stirred at 70° C. for 2hours. The reaction was cooled to room temperature and concentrated invacuo. The crude urea was purified by chromatography (Biotage: 85%CHCl₃, 14% MeOH, 1% NH₄OH). The product was then treated withN,N-dimethylformamide (20 mL) and N,N′-diisopropylcarbodiimide (0.67 mL,4.28 mmol). The reaction was heated to 70° C. for 2 hours. The reactionwas cooled to room temperature and concentrated in vacuo to yield thecrude product. The crude product was purified by chromatography(Biotage: 85% CHCl₃, 14% MeOH, 1% NH₄OH) to yield(R)-6-(4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]-2-ylamino)-2-methylnicotinonitrile(0.09 g, 0.3 mmol, 21% yield) as a white powder. 1H NMR (500 MHz,DMSO-D6) δ ppm 9.11 (s, 1H), 7.87 (d, J=7.93 Hz, 2H), 6.69 (s, 1H), 3.89(d, J=10.38 Hz, 2H), 3.63 (d, J=10.38 Hz, 3H), 3.00 (s, 5H), 2.72-2.80(m, 4H), 2.64-2.69 (m, 5H), 2.60 (s, 7H), 2.00 (d, J=2.14 Hz, 3H), 1.91(s, 1H), 1.87 (s, 2H), 1.58 (s, 5H), 1.42-1.50 (m, 2H). MS (LC/MS)R.T.=0.48; [M+H]⁺=298.13.

Example 248(R)-6-(4H-1′-Azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]-2-ylamino)-2,4-dimethylnicotinonitrile

Step A: 6-Isothiocyanato-2,4-dimethylnicotinonitrile

To 6-amino-2,4-dimethylnicotinonitrile (0.14 g, 0.95 mmol) indichloromethane (20 mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one(0.23 g, 0.1 mmol). The reaction was stirred at 40° C. for 3 hours. Thereaction was cooled to room temperature. The crude was purified bychromatography (Biotage: 25-100% ethyl acetate/hexane) to yield6-isothiocyanato-2,4-dimethylnicotinonitrile (0.15 g, 0.79 mmol, 83%yield). 1H NMR (500 MHz, DMSO-D6) δ ppm 7.37 (s, 1H), 2.63 (s, 3H). MS(LC/MS) R.T.=2.40; [M+H]⁺=190.

Step B:(R)-6-(4H-1′-Azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]-2-ylamino)-2,4-dimethylnicotinonitrile

To 6-isothiocyanato-2,4-dimethylnicotinonitrile (0.09 g, 0.48 mmol) inN,N-dimethylformamide (20 mL) was added triethylamine (0.17 mL, 1.19mmol) and 3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.11 g, 0.49mmol) at room temperature. The reaction was stirred at 70° C. for 2hours. The reaction was cooled to room temperature and concentrated invacuo. The crude urea was purified by chromatography (Biotage: 85%CHCl₃, 14% MeOH, 1% NH₄OH). The product was then treated withN,N-dimethylformamide (20 mL) and N,N′-diisopropylcarbodiimide (0.22 mL,1.43 mmol). The reaction was heated to 70° C. for 2 hours. The reactionwas cooled to room temperature and concentrated in vacuo to yield thecrude product. The crude product was purified by chromatography(Biotage: 85% CHCl₃, 14% MeOH, 1% NH₄OH) to yield(R)-6-(4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]-2-ylamino)-2,4-dimethylnicotinonitrile(0.10 g, 0.32 mmol, 66% yield) as a white powder. 1H NMR (500 MHz,DMSO-D6) δ ppm 9.08 (s, 1H), 6.60 (s, 1H), 3.88 (d, J=10.38 Hz, 1H),3.61 (d, J=10.38 Hz, 1H), 2.98 (s, 2H), 2.70-2.79 (m, 2H), 2.63-2.69 (m,2H), 2.55-2.60 (m, 4H), 2.31-2.39 (m, 4H), 1.99 (s, 1H), 1.89 (s, 1H),1.54-1.62 (m, 2H), 1.41-1.49 (m, 1H). MS (LC/MS) R.T.=0.78;[M+H]⁺=312.1.

Example 249(R)—N-(6-Phenylpyridazin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 3-Isothiocyanato-6-phenylpyridazine

3-Isothiocyanato-6-phenylpyridazine was synthesized by the method ofExample 23, Step B. Flash chromatography on a 120 g silica gel cartridgewith 0 to 25% EtOAc in hexane, 25 min, at 35 mL/min afforded 420 mg (49%yield).

LCMS: RT=2.17 min, MH+=214.06.

Step B:(R)—N-(6-Phenylpyridazin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(6-Phenylpyridazin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas synthesized by the method of Example 23, Step B. Flashchromatography on a 160 g silica gel cartridge with 1-4% [9:1MeOH/NH₄OH] in CHCl₃, 50 min, at 40 mL/min afforded 67 mg(R)—N-(6-phenylpyridazin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(17% yield).

1H NMR (400 MHz, CDCl₃) δ ppm 9.61 (1H, br. s.), 7.95-7.99 (2H, m), 7.74(1H, d, J=9.32 Hz), 7.39-7.52 (3H, m), 7.22 (1H, partial d), 3.97 (1H,d, J=9.32 Hz), 3.64 (1H, d, J=9.32 Hz), 3.37 (1H, dd, J=14.73, 1.38 Hz),2.69-3.06 (5H, m), 2.16-2.26 (1H, m), 2.14 (1H, br. s.), 1.66-1.79 (1H,m), 1.45-1.60 (2H, m)

1H NMR (400 MHz, MeOD) δ ppm 7.87-8.02 (3H, m), 7.44-7.55 (3H, m),7.13-7.29 (1H, m), 4.05 (1H, d, J=9.82 Hz), 3.74 (1H, d, J=10.07 Hz),3.17 (2H, dd, J=49.35, 14.60 Hz), 2.73-3.04 (4H, m), 2.16 (2H, br. s.),1.55-1.85 (3H, m)

LCMS: RT=0.82 min, MH−=334.2, MH+=336.2.

Example 250(R)—N-(5-(Methylthio)pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 5-(Methylthio)pyrazin-2-amine

To a solution of 5-bromopyrazin-2-amine (2 g, 11.49 mmol) inN,N-dimethylformamide (20 ml) was added sodium thiomethoxide (1.611 g,22.99 mmol). The mixture was stirred and heated at 100° C. undernitrogen for 18 h and concentrated. The residue was treated with waterand the mixture was extracted with dichloromethane. The combinedorganics were dried with sodium sulfate, filtered and concentrated. Theresidue was purified by silica gel chromatography (0-10% 9:1 methanol:ammonium hydroxide-ethyl acetate) to afford6-(pyridin-3-yl)pyrimidin-4-amine (0.15 g, 0.871 mmol, 35% yield) as ayellow solid. LCMS R.T.=0.91; [M+H]⁺=141.89.

Step B: 2-Isothiocyanato-5-(methylthio)pyrazine

To a solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (1.069 g, 4.60mmol) in dichloromethane at room temperature was added5-(methylthio)pyrazin-2-amine (0.50 g, 3.54 mmol). The reaction wasstirred at room temperature for 18 hours. LC/MS showed the desiredproduct peak as the major peak. The deep orange mixture was purified bysilica gel chromatography (0-40% ethyl acetate-hexanes) to afford2-isothiocyanato-5-(methylthio)pyrazine (0.545 g, 0.257 mmol, 84% yield)as an orange oil. LCMS R.T.=2.65; [M+H]⁺=184.02.

Step C:(R)—N-(5-(Methylthio)pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.375 g, 1.637mmol) in N,N-dimethylformamide (15 mL) was added Cs₂CO₃ (1.333 g, 4.09mmol) and 2-isothiocyanato-5-(methylthio)pyrazine (0.3 g, 1.637 mmol).The suspension was stirred at room temperature for 30 minutes.N,N′-diisopropylcarbodiimide (0.765 mL, 4.9 mmol) was then added and themixture was continued to stir at room temperature for 18 hours. Themixture was concentrated and purified by silica gel chromatography(5-25% 9:1 methanol:ammonium hydroxide-ethyl acetate) to afford(R)—N-(5-(methylthio)pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.014 g, 0.04 mmol, 16% yield) as a yellow solid. M.P. 155-60° C. ¹HNMR (400 MHz, MeOD) δ ppm 8.13 (1H, d), 8.06 (1H, s), 3.96 (1H, d), 3.66(1H, d), 3.20 (1H, d), 3.08 (1H, d), 2.87-2.96 (2H, m), 2.72-2.82 (2H,m), 2.52 (3H, s), 2.00-2.19 (2H, m), 1.51-1.81 (3H, m). LCMS R.T.=1.01;[M+H]⁺=306.12.

Example 251(R)—N-(5,6-Dichloropyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: N-(5,6-Dichloropyridin-2-yl)pivalamide

To a solution of N-(6-chloropyridin-2-yl)pivalamide, synthesized as inJ. Org. Chem 2005, 70, 1771, (1.02 g, 4.80 mmol) in chloroform (25 mL)was added 1-chloropyrrolidine-2,5-dione (0.62 g, 4.67 mmol) and themixture was refluxed in an oil bath for 3 hrs. It was allowed to cool toroom temperature overnight. The reaction mixture was evaporated in vacuoand re-dissolved in DMF (15 mL). Another 480 mg1-chloropyrrolidine-2,5-dione was added and the resulting solution washeated overnight in an oil bath at 95-100°, then cooled again to roomtemperature. The solvent was removed in vacuo and the residue waspartitioned between water and ethyl acetate. The aqueous phase waswashed twice more with ethyl acetate and the combined organic phaseswere washed with brine, dried over magnesium sulfate, and evaporated invacuo. TLC (10% ethyl acetate/hexane) showed a robust spot at Rf 0.6with smaller spots at Rf 0.4 and 0.2. The material was subjected to theBiotage in 5-10% ethyl acetate/hexane, collecting the Rf 0.6 fraction togive 790 mg (66%) white solid, N-(5,6-dichloropyridin-2-yl)pivalamide.1H NMR (500 MHz, CDCl₃) δ ppm 8.17 (s, 1H), 7.96 (s, 1H), 7.72 (s, 1H),1.31 (s, 10H). MS (LC/MS) R.T.=1.85; [M+H]⁺=248.8.

Step B: 5,6-Dichloropyridin-2-amine

A mixture of N-(5,6-dichloropyridin-2-yl)pivalamide (790 mg, 3.20 mmol),hydrochloric acid, 37% (1.25 mL), water (1.25 mL), and EtOH (3 mL) washeated for 4 hrs in an oil bath at 85-90° C. LCMS showed nearly completeconversion to product. The reaction was cooled to room temperature andthe reaction mixture was evaporated down to a small volume, thentransferred to a separatory funnel where it was partitioned betweenaqueous sodium carbonate and ethyl acetate. The layers were separated,the aqueous phase was washed again with ethyl acetate, and the combinedorganic phases were washed with brine, dried over MgSO₄, filtered, andevaporated to give a white solid. The material was subjected to aBiotage column in 20% ethyl acetate/hexane, collecting the maincomponent. 5,6-Dichloropyridin-2-amine (0.49 g, 2.98 mmol, 93%) wasobtained as a white solid. 1H NMR (500 MHz, CDCl₃) δ ppm 7.44 (d, J=8.55Hz, 1H), 6.36 (d, J=8.24 Hz, 1H), 4.58 (s, 2H). MS (LC/MS) R.T.=1.28;[M+H]⁺=164.8.

Step C: 5,6-Dichloro-2-isothiocyanatopyridine

To 5,6-dichloropyridin-2-amine (0.47 g, 2.88 mmol) in dichloromethane(25 mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one (0.68 g, 2.94mmol). The reaction was stirred at 40° C. for 3 hours, then cooled toroom temperature. The crude material was purified by chromatography(Biotage: 25-100% ethyl acetate/hexane)2,3-dichloro-6-isothiocyanatopyridine (0.48 g, 2.34 mmol, 81% yield) asa white powder. 1H NMR (500 MHz, DMSO-D6) δ ppm 8.26 (d, J=8.55 Hz, 1H),7.47 (d, J=8.24 Hz, 1H). MS (LC/MS) R.T.=2.83; [M+H]⁺=204.8.

Step D:(R)—N-(5,6-Dichloropyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To 2,3-dichloro-6-isothiocyanatopyridine (0.47 g, 2.29 mmol) inN,N-dimethylformamide (20 mL) was added triethylamine (0.8 mL, 5.7 mmol)and 3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.54 g, 2.34 mmol)at room temperature. The reaction was stirred at 70° C. for 2 hours,cooled to room temperature and concentrated in vacuo. The crude urea waspurified by chromatography (Biotage: 85% CHCl₃, 14% MeOH, 1% NH₄OH). Theproduct was then treated with N,N-dimethylformamide (20 mL) andN,N′-diisopropylcarbodiimide (1.07 mL, 6.88 mmol). The reaction washeated to 70° C. for 2 hours. The reaction was cooled to roomtemperature and concentrated in vacuo. The crude product was purified bychromatography (Biotage: 85% CHCl₃, 14% MeOH, 1% NH₄OH) to yield(R)—N-(5,6-dichloropyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.36 g, 1.08 mmol, 47% yield) as a white powder. 1H NMR (500 MHz,DMSO-D6) δ ppm 8.31 (d, J=1.22 Hz, 1H), 7.84 (s, 1H), 6.80 (s, 1H), 3.85(d, J=10.07 Hz, 1H), 3.57 (d, J=10.38 Hz, 2H), 2.98 (s, 3H), 2.69-2.78(m, 3H), 2.65 (t, J=7.78 Hz, 3H), 2.00 (s, 2H), 1.86 (s, 2H), 1.58 (dd,J=7.48, 2.90 Hz, 2H), 1.56 (s, 1H), 1.41-1.49 (m, 2H). MS (LC/MS)R.T.=0.81; [M+H]⁺=327.1.

Example 252(R)—N-(4,5-Dichloropyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 4,5-Dichloro-2-isothiocyanatopyridine

To 4,5-dichloropyridin-2-amine (0.25 g, 1.53 mmol) in dichloromethane(25 mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one (0.36 g, 1.56mmol). The reaction was stirred at 40° C. for 3 hours, then cooled toroom temperature. The crude material was purified by chromatography(Biotage: 25-100% ethyl acetate/hexane) to yield4,5-dichloro-2-isothiocyanatopyridine (0.26 g, 1.27 mmol, 83% yield) asa yellow powder. The product was carried directly to the next step.

Step B:(R)—N-(4,5-Dichloropyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To 4,5-dichloro-2-isothiocyanatopyridine (0.25 g, 1.22 mmol) inN,N-dimethylformamide (20 mL) was added triethylamine (0.43 mL, 3.05mmol) and (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.29 g,1.24 mmol) at room temperature. The reaction was stirred at 70° C. for 2hours. The reaction was cooled to room temperature and concentrated invacuo. The crude urea was purified by chromatography (Biotage: 85%CHCl₃, 14% MeOH, 1% NH₄OH). The product was then treated withN,N-dimethylformamide (20 mL) and N,N′-diisopropylcarbodiimide (0.57 mL,3.66 mmol). The reaction was heated to 70° C. for 2 hours. The reactionwas cooled to room temperature and concentrated to yield the crudeproduct. The crude product was purified by chromatography (Biotage: 85%CHCl₃, 14% MeOH, 1% NH₄OH) to yield(R)—N-(4,5-dichloropyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.09 g, 0.27 mmol, 22% yield) as a white powder. 1H NMR (500 MHz,DMSO-D6) δ ppm 8.81 (s, 1H), 8.32 (d, J=6.10 Hz, 1H), 7.03 (s, 1H), 3.83(d, J=9.46 Hz, 1H), 3.57 (d, J=9.77 Hz, 1H), 2.98 (s, 2H), 2.71-2.79 (m,2H), 2.65 (t, J=7.78 Hz, 2H), 1.99 (s, 1H), 1.86 (s, 1H), 1.53-1.61 (m,2H), 1.41-1.49 (m, 1H). MS (LC/MS) R.T.=0.78; [M+H]⁺=327.0.

Example 253(R)—N-(5-Chloro-4-methylpyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 5-Chloro-2-isothiocyanato-4-methylpyridine

To 5-chloro-4-methylpyridin-2-amine (0.41 g, 2.88 mmol) indichloromethane (25 mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one(0.70 g, 3.0 mmol). The reaction was stirred at 40° C. for 3 hours. Thereaction was cooled to room temperature. The crude mixture was purifiedby chromatography (Biotage: 25-100% ethyl acetate/hexane) to yield5-chloro-2-isothiocyanato-4-methylpyridine (0.45 g, 2.44 mmol, 85%yield). 1H NMR (500 MHz, DMSO-D6) δ ppm 8.45 (s, 1H), 7.47 (s, 1H), 2.37(s, 3H). LC/MS RT=2.79; [M+H]⁺=184.9.

Step B:(R)—N-(5-Chloro-4-methylpyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To 5-chloro-2-isothiocyanato-4-methylpyridine (0.37 g, 2.0 mmol) inN,N-dimethylformamide (20 mL) was added triethylamine (0.7 mL, 5.0 mmol)and (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (from Step B ofExample 17) (0.47 g, 2.0 mmol) at room temperature. The reaction wasstirred at 70° C. for 2 hours. The reaction was cooled to roomtemperature and concentrated in vacuo. The crude urea was purified bychromatography (Biotage: 85% CHCl₃, 14% MeOH, 1% NH₄OH). The product wasthen treated with N,N-dimethylformamide (20 mL) andN,N′-diisopropylcarbodiimide (0.94 mL, 6.0 mmol). The reaction washeated to 70° C. for 2 hours. The reaction was cooled to roomtemperature and concentrated to yield the crude product. The crudeproduct was purified by chromatography (Biotage: 85% CHCl₃, 14% MeOH, 1%NH₄OH) to yield(R)—N-(5-chloro-4-methylpyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.19 g, 0.61 mmol, 30.3% yield) as a white powder. 1H NMR (500 MHz,DMSO-D6) δ ppm 8.79 (s, 1H), 8.08-8.15 (m, 2H), 6.78 (s, 1H), 3.82 (d,J=8.55 Hz, 2H), 3.55 (d, J=10.38 Hz, 2H), 2.93-3.02 (m, 5H), 2.71-2.80(m, 5H), 2.66 (t, J=7.63 Hz, 4H), 2.23-2.29 (m, 7H), 1.94-2.02 (m, 2H),1.92 (s, 1H), 1.86 (s, 2H), 1.53-1.62 (m, 5H), 1.41-1.49 (m, J=12.55,9.88, 7.02, 2.29 Hz, 2H). MS (LC/MS) R.T.=0.72; [M+H]⁺=307.1.

Example 254(R)—N-(6-Chloropyridazin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 3-Chloro-6-isothiocyanatopyridazine

3-Chloro-6-isothiocyanatopyridazine was synthesized by the method ofExample 218, Step D. Flash chromatography on a 120 g silica gelcartridge with 0 to 25% EtOAc in hexane, 25 min, at 35 mL/min afforded213 mg (31% yield).

LCMS: RT=1.25 min, MH+=172.00.

Step B:(R)—N-(6-Chloropyridazin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(6-Chloropyridazin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas synthesized by the method of Example 218, Step E. Flashchromatography on a 160 g silica gel cartridge with 1-3% [9:1MeOH/NH4OH] in CHCl3, 50 min, at 40 mL/min afforded 29 mg (8% yield).

1H NMR (400 MHz, CDCl₃) δ ppm 9.27 (1H, br. s.), 7.28 (1H, d, J=9.07Hz), 7.10 (1H, d, J=9.07 Hz), 3.95 (1H, d, J=9.57 Hz), 3.62 (1H, d,J=9.57 Hz), 3.34 (1H, dd, J=14.98, 1.64 Hz), 2.67-3.04 (5H, m),2.14-2.21 (1H, m), 2.12 (1H, br. s.), 1.65-1.79 (1H, m), 1.45-1.61 (2H,m).

LCMS: RT=0.62 min, MH−=292.1, MH+=294.1.

Example 255(R)—N-(6-Bromopyridazin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 3-Bromo-6-isothiocyanatopyridazine

3-Bromo-6-isothiocyanatopyridazine was synthesized by the method ofExample 218, Step D. Flash chromatography on a 120 g silica gelcartridge with 0 to 25% EtOAc in hexane, 25 min, at 35 mL/min afforded364 mg (42% yield).

LCMS: RT=1.34 min, MH+=215.92.

Step B:(R)—N-(6-Bromopyridazin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(6-Bromopyridazin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas synthesized by the method of Example 218, Step E. Flashchromatography on a 160 g silica gel cartridge with 1-3% [9:1MeOH/NH4OH] in CHCl3, 50 min, at 40 mL/min afforded 211 mg (37% yield).

1H NMR (400 MHz, CDCl₃) δ ppm 9.23 (1H, br. s.), 7.37 (1H, d, J=9.07Hz), 6.97 (1H, d, J=9.07 Hz), 3.92 (1H, d, J=9.57 Hz), 3.59 (1H, d,J=9.82 Hz), 3.29 (1H, dd, J=14.98, 1.64 Hz), 2.63-2.99 (5H, m),2.04-2.19 (2H, m), 1.59-1.74 (1H, m), 1.39-1.58 (2H, m)

LCMS: RT=0.64 min., MH-336.1, MH+338.0.

Example 256(R)—N-(6-(4-Chlorophenyl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 6-(Pyridin-4-yl)pyrimidin-4-amine

A mixture of 6-chloropyrimidin-4-amine (0.324 g, 2.5 mmol),4-chlorophenylboronic acid (0.489 g, 3.13 mmol), Na₂CO₃ (0.795 g, 7.50mmol) and bis(triphenylphosphine)palladium(II) chloride (0.035 g, 0.050mmol) was suspended in a mixture of DME/EtOH/water (15:2:3 mL). Themixture was heated in the microwave synthesizer at 125° C. for 20 minand concentrated. The residue was purified by silica gel chromatography(2-15% 9:1 methanol:ammonium hydroxide-ethyl acetate) toafford:6-(pyridin-3-yl)pyrimidin-4-amine (0.3 g, 0.871 mmol, 58.4%yield) as an off-white solid. LCMS R.T.=1.42; [M+2H]⁺=207.91.

Step B: 4-(4-Chlorophenyl)-6-isothiocyanatopyrimidine

To a bright orange solution of 1,1′-thiocarbonyldipyridin-2(1H)-one(0.666 g, 2.87 mmol) dichloromethane/N,N-dimethylformamide at roomtemperature was added 6-(4-chlorophenyl)pyrimidin-4-amine (0.59 g, 2.87mmol). The orange mixture was heated at 60° C. for 18 hours. The LC/MSshowed the desired product peak as a major peak. The deep orange mixturewas purified by silica gel chromatography (0-40% ethyl acetate-hexanes)to afford 4-(4-chlorophenyl)-6-isothiocyanatopyrimidine (0.322 g, 1.300mmol, 45% yield) as an orange oil. LCMS R.T.=2.82; [M]′=248.03.

Step C:(R)—N-(6-(4-Chlorophenyl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.298 g, 1.300mmol) in N,N-dimethylformamide (15 mL) was added Cs₂CO₃ (1.059 g, 3.25mmol) and 4-(4-chlorophenyl)-6-isothiocyanatopyrimidine (0.322 g, 1.300mmol). The suspension was stirred at room temperature for 30 minutes.N,N′-Diisopropylcarbodiimide (0.608 mL, 3.90 mmol) was then added andthe mixture was stirred at room temperature for 18 hours. The mixturewas concentrated and purified by silica gel chromatography (5-25% 9:1methanol:ammonium hydroxide-ethyl acetate) to afford(R)—N-(6-(pyridin-4-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.104 g, 0.276 mmol, 21% yield) as a yellow solid. ¹H NMR (400 MHz,CDCl₃) δ ppm 9.54 (1H, br. s.), 8.83 (1H, d), 7.89-8.04 (2H, m),7.41-7.54 (2H, m), 7.33 (1H, br. s.), 4.02 (1H, d), 3.71 (1H, d), 3.42(1H, d), 2.73-3.15 (5H, m), 2.10-2.31 (2H, m), 1.46-1.89 (3H, m). LCMSR.T.=1.92; [M]⁺=370.35.

Example 257(R)—N-(6-(3-Chlorophenyl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 6-(3-Chlorophenyl)pyrimidin-4-amine

A mixture of 6-chloropyrimidin-4-amine (0.324 g, 2.5 mmol),3-chlorophenylboronic acid (0.489 g, 3.13 mmol), Na₂CO₃ (0.795 g, 7.50mmol) and bis(triphenylphosphine)palladium(II) chloride (0.035 g, 0.050mmol) was suspended in a mixture of DME/EtOH/water (15:2:3 mL). Themixture was heated in the microwave synthesizer at 125° C. for 20 minand concentrated. The residue was purified by silica gel chromatography(30-70% ethyl acetate in hexanes) to afford:6-(3-chlorophenyl)pyrimidin-4-amine (0.47 g, 2.286 mmol, 91% yield) as ayellow solid. LCMS R.T.=1.45; [M+2H]⁺=208.05.

Step B: 4-(3-Chlorophenyl)-6-isothiocyanatopyrimidine

To a bright orange solution of 1,1′-thiocarbonyldipyridin-2(1H)-one(0.486 g, 2.091 mmol) in dichloromethane/N,N-dimethylformamide at roomtemperature was added 6-(3-chlorophenyl)pyrimidin-4-amine (0.43 g, 2.091mmol). The orange mixture was heated at 60° C. for 18 hours. The LC/MSshowed the desired product peak as a major peak. The deep orange mixturewas purified by silica gel chromatography (0-40% ethyl acetate-hexanes)to afford 4-(3-chlorophenyl)-6-isothiocyanatopyrimidine (0.12 g, 0.484mmol, 23% yield) as an orange oil. LCMS R.T.=2.15; [M]′=248.31.

Step C:(R)—N-(6-(3-Chlorophenyl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.111 g, 0.484mmol) in N,N-dimethylformamide (15 mL) was added Cs₂CO₃ (0.395 g, 1.211mmol) and 4-(3-chlorophenyl)-6-isothiocyanatopyrimidine (0.12 g, 0.484mmol). The suspension was stirred at room temperature for 30 minutes.N,N′-diisopropylcarbodiimide (0.226 mL, 1.453 mmol) was then added andthe mixture was continued to stir at room temperature for 18 hours. Themixture was concentrated and purified by silica gel chromatography(5-25%, then, 2-10% 9:1 methanol:ammonium hydroxide-ethyl acetate) toafford(R)—N-(6-(3-chlorophenyl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.086 g, 0.221 mmol, 46% yield) as a yellow solid. ¹H NMR (400 MHz,MeOD) δ ppm 8.82 (1H, d), 8.05 (1H, d), 7.93 (1H, ddd), 7.43-7.52 (2H,m), 7.35 (1H, br. s.), 4.13 (1H, d), 3.93 (1H, d), 3.63-3.81 (2H, m),3.42-3.53 (1H, m), 3.30-3.40 (3H, m), 2.46 (1H, d), 2.26-2.40 (1H, m),1.88-2.16 (3H, m). LCMS R.T.=1.90; [M]⁺=370.28.

Example 258(R)—N-(5-Methyl-1,3,4-oxadiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: Dimethyl 5-methyl-1,3,4-oxadiazol-2-ylcarbonimidodithioate

To a solution of 5-methyl-1,3,4-oxadiazol-2-amine (1.92 g, 20 mmol) inDMF (10 ml) was added NaOH (20M, 2 ml), CS₂ (3 ml), NaOH (20M, 2 ml) andiodomethane (3 ml) slowly over 10 minutes. The mixture was stirred atroom temperature for 1 h and poured into 20 ml water. The precipitatedsolid was filtered, washed with water, and dried to obtain the desiredproduct, dimethyl 5-methyl-1,3,4-oxadiazol-2-ylcarbonimidodithioate as awhite solid (1.45 g, 35.7%). ¹H NMR (500 MHz, CDCl₃) δ ppm 2.63 (s, 6H),2.50 (s, 3H). LCMS R.T. 1.66 min; [M+H]=203.91.

Step B:(R)—N-(5-Methyl-1,3,4-oxadiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

A mixture of dimethyl 5-methyl-1,3,4-oxadiazol-2-ylcarbonimidodithioate(260 mg, 1.28 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride(200 mg, 1.28 mmol) and cesium carbonate (876 mg, 2.69 mmol) in DMF (5ml) was stirred overnight at room temperature. The mixture wasconcentrated and purified on a Biotage silica gel column (100% ethylacetate, then 10-35% 9:1 methanol:ammonium hydroxide-chloroform) toobtain the desired product,(R)—N-(5-methyl-1,3,4-oxadiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(192 mg, 54.1%). ¹H NMR (500 MHz, MeOD) δ ppm 4.05 (d, 1H), 3.74 (d,1H), 3.25 (d, 1H), 3.15 (d, 1H), 2.94 (m, 2H), 2.85 (m, 2H), 2.43 (s,3H), 2.19 (m, 1H), 2.10 (m, 1H), 1.6-1.8 (m, 3H). MS (LCMS)[M+H]=264.05. R.T. 0.16 min.

Example 259(R)—N-(3-Methyl-1,2,4-thiadiazol-5-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: Dimethyl 3-methyl-1,2,4-thiadiazol-5-ylcarbonimidodithioate

To a solution of 3-methyl-1,2,4-thiadiazol-5-amine (2.3 g, 20 mmol) inDMF (10 ml) was added NaOH (20M, 2 ml), CS₂ (3 ml), NaOH (20M, 2 ml) andiodomethane (3 ml) slowly over 10 minutes. The mixture was stirred atroom temperature for 1 h and poured into 20 ml water. The precipitatedsolid was filtered and washed with water, and dried to obtain impuredimethyl 3-methyl-1,2,4-thiadiazol-5-ylcarbonimidodithioate, a yellowsolid (2.3 g, 52.5%). ¹H NMR (500 MHz, CDCl3) δ ppm 2.67 (s), 2.62 (s).MS [M+H]=219.85.

Step B:(R)—N-(3-Methyl-1,2,4-thiadiazol-5-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

A mixture of dimethyl 3-methyl-1,2,4-thiadiazol-5-ylcarbonimidodithioate(281 mg, 1.28 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride(200 mg, 1.28 mmol) and cesium carbonate (876 mg, 2.69 mmol) in DMF (5ml) was stirred overnight at room temperature. The mixture wasconcentrated and purified on a Biotage silica gel column (100% ethylacetate, then 10-35% 9:1 methanol:ammonium hydroxide-chloroform) toobtain the desired product,(R)—N-(3-methyl-1,2,4-thiadiazol-5-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(147.8 mg, 40.5%). ¹H NMR (500 MHz, MeOD) δ ppm 4.01-3.99 (d, 1H),3.72-3.70 (d, 1H), 3.27 (d, 1H), 3.16 (d, 1H), 3.01-2.9 (m, 2H),2.86-2.83 (m, 2H), 2.43 (s, 3H), 2.21-2.0 (m, 2H), 1.81-1.75 (m, 1H),1.75-1.70 (m, 2H). MS (LCMS) [M+H]=279.99; R.T.=0.2 min.

Example 260(R)—N-(3-Methyl-1,2,4-oxadiazol-5-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: Dimethyl 3-methyl-1,2,4-oxadiazol-5-ylcarbonimidodithioate

To a solution of 3-methyl-1,2,4-oxadiazol-5-amine (490 mg, 4.94 mmol) inDMF (5 ml) was added NaOH (20M, 0.5 ml), CS₂ (1 ml), NaOH (20M, 0.5 ml)and iodomethane (1 ml) slowly over 10 minutes. The mixture was stirredat room temperature for 1 hour. The mixture became very thick, and 20 mlwater was added. The solid was filtered off, washed with water, anddried to obtain impure dimethyl3-methyl-1,2,4-oxadiazol-5-ylcarbonimidodithioate, a yellow solid (770mg, 77%).

MS (LCMS) [M+H]=203.91; R.T.=1.84 min. The product was used directly inthe next step.

Step B:(R)—N-(3-Methyl-1,2,4-oxadiazol-5-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

A mixture of dimethyl 3-methyl-1,2,4-oxadiazol-5-ylcarbonimidodithioate(280 mg, 1.37 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride(215 mg, 1.37 mmol) and cesium carbonate (942 mg, 2.89 mmol) in DMF (5ml) was stirred overnight at room temperature. The mixture wasconcentrated and purified on a Biotage silica gel column (100% ethylacetate, then 10-35% 9:1 methanol:ammonium hydroxide-chloroform) toobtain the desired product,(R)—N-(3-methyl-1,2,4-oxadiazol-5-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(198 mg, 51.9%). ¹H NMR (500 MHz, MeOD) δ ppm 4.1-4.0 (d, 1H), 3.8-3.7(d, 1H), 3.4-3.2 (d, 1H), 3.2-3.1 (d, 1H), 3.0-2.9 (m, 2H), 2.9-2.8 (m,2H), 2.27 (s, 3H), 2.2 (m, 1H), 2.2-2.0 (m, 1H), 1.9-1.6 (m, 3H). MS(LCMS) [M+H]=264.05; R.T.=0.26 min.

Example 261(R)—N-(6-(Methylthio)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: Dimethyl 6-chloropyrimidin-4-ylcarbonimidodithioate

To a solution of 6-chloropyrimidin-4-amine (1.295 g, 10 mmol) inN,N-dimethylformamide (12 mL) was added dropwise NaOH (1 mL, 20.00 mmol,20 M), CS2 (1.5 mL, 24.88 mmol), NaOH (1 mL, 20.00 mmol, 20 M) andiodomethane (1.5 mL, 23.99 mmol) at 15 min intervals. Stirring wascontinued for 1.5 h and the mixture was poured into water. The orangesolid was separated washed with water, dried and recrystallised frommethanol to afford dimethyl 6-chloropyrimidin-4-ylcarbonimidodithioate(0.966 g, 4.13 mmol, 41.3% yield) as a yellow solid. LCMS R.T.=2.39;[M+H]⁺=234.08.

Step B:(R)—N-(6-(Methylthio)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.9 g, 3.93mmol) in N,N-dimethylformamide (20 mL) was added Cs₂CO₃ (2.69 g, 8.25mmol) and dimethyl 6-chloropyrimidin-4-ylcarbonimidodithioate (0.964 g,4.12 mmol). The suspension was stirred at room temperature for 18 hours,then heated at 100 C for 3 hours. The mixture was concentrated andpurified by silica gel chromatography (5-15% 9:1 methanol:ammoniumhydroxide-ethyl acetate) to afford(R)—N-(6-(methylthio)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.21 g, 0.72 mmol, 48.2% yield) as a pale yellow solid. ¹H NMR (400MHz, CDCl₃) δ ppm 9.43 (1H, br. s.), 8.55 (1H, d), 6.78 (1H, br. s.),3.98 (1H, d), 3.64 (1H, d), 3.37 (1H, dd), 2.72-3.06 (5H, m), 2.51 (3H,s), 2.08-2.24 (2H, m), 1.69-1.81 (1H, m), 1.41-1.64 (2H, m). LCMSR.T.=0.93; [M+H]⁺=306.29.

Example 262(R)—N-([1,2,4]Triazol[4,3-a]pyridine-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: Di(1H-imidazol-1-yl)methanimine

To a solution of 1H-imidazole (42 g, 617 mmol) in dichloromethane (1 L)was added cyanogen bromide (22.5, 212 mmol) and the mixture was heatedto reflux for 30 minutes, allowed to cool to room temperature and thewhite solid was filtered off. The filtrate was concentrated to 100 mland stored in the refrigerator for 3 days. The precipitated solid wasfiltered off to obtain 8 g di(1H-imidazol-1-yl)methanimine (49.6 mmol,8%). ¹H NMR (500 MHz, DMSO) δ ppm 8.09 (s, 1H), 7.55 (s, 1H), 7.13 (s,1H).

Step B: [1,2,4]Triazolo[4,3-a]pyridine-3-amine

To a solution of 2-hydrazinylpyridine (5.2 g, 47.6 mmol) in THF (70 ml)was added di(1H-imidazol-1-yl)methanimine (7.8 g, 48.4 mmol). Themixture was heated to reflux overnight. The crude mixture was evaporatedand purified on a Biotage silica gel column (0-25%, methanol-methylenechloride) collecting the purple-colored spot,[1,2,4]triazolo[4,3-a]pyridine-3-amine (4.7 g, 35 mmol, 73.5%). ¹H NMR(500 MHz, DMSO) δ ppm 8.05-8.0 (m, 1H), 7.44-7.40 (m, 1H), 7.08-7.0 (m,1H), 6.74-6.70 (m, 1H), 6.35 (s, 2H). MS (LCMS) [M+H]=134.98; R.T.=0.1min.

Step C: Dimethyl[1,2,4]triazol[4,3-a]pyridine-3-ylcarbonimidodithioate

To a solution of [1,2,4]triazolo[4,3-a]pyridine-3-amine (300 mg, 2.24mmol) in DMF (5 ml) was added NaOH (20M, 0.25 ml), CS₂ (0.5 ml), NaOH(20M, 0.25 ml) and iodomethane (0.5 ml) slowly over 10 minutes. Themixture was stirred at room temperature for 1 h and 10 ml water wasadded to the reaction mixture. The precipitated solid was filtered off,washed with water (100 ml), and dried to obtain 230 mgdimethyl[1,2,4]triazol[4,3-a]pyridine-3-ylcarbonimidodithioate (0.96mmol, 43.1%), a white solid. ¹H NMR (500 MHz, CDCl3) δ ppm 8.17 (d, 1H),7.7 (d, 1H), 7.24-7.22 (t, 1H), 6.84-6.80 (t, 1H), 2.71-2.68 (d, 6H). MS(LCMS) [M+H]=238.94; R.T.=1.26 min.

Step D.(R)—N-([1,2,4]Triazol[4,3-a]pyridine-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

A mixture ofdimethyl[1,2,4]triazol[4,3-a]pyridine-3-ylcarbonimidothioate (120 mg,0.50 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (120 mg,0.76 mmol) and cesium carbonate (492 mg, 1.5 mmol) in DMF (5 ml) washeated at 70° C. for 6 hours. The mixture was concentrated and purifiedon a Biotage silica gel column (100% ethyl acetate, then 10-35% 9:1methanol:ammonium hydroxide-chloroform) to obtain the desired product,(R)—N-([1,2,4]triazol[4,3-a]pyridine-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(97.2 mg, 61.5%). ¹H NMR (500 MHz, CDCl3) δ ppm 8.2-8.1 (d, 1H), 7.6-7.5(d, 1H), 7.2-7.1 (t, 1H), 6.7-6.6 (t, 1H), 4.1-4.0 (d, 1H), 3.7-3.6 (d,1H), 3.5-3.4 (m, 1H), 3.1-2.7 (m, 5H), 2.4-2.2 (m, 2H), 1.8-1.7 (m, 1H),1.7-1.5 (m, 2H). MS (LCMS) [M+H]=299.3; R.T.=1.22 min.

Example 263(R)—N-(6-bromothiazolo[5,4-b]pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: Dimethyl 6-bromothiazolo[5,4-b]pyrazin-2-ylcarbonimidodithioate

To a suspension of 6-bromothiazolo[5,4-b]pyrazin-2-amine (700 mg, 3.03mmol) in DMF (3 mL) was added 16.0M sodium hydroxide (400 μL, 6.40mmol). The mixture was allowed to stir 10 min at room temperature atwhich time carbon disulfide was added (450 μL, 7.57 mmol) and theresulting reddish brown mixture was stirred for 10 minutes. Anadditional portion of 16.0M sodium hydroxide (400 μL, 6.40 mmol) wasadded and the mixture was again stirred for 10 minutes. Finally,iodomethane (450 μL, 7.27 mmol) was added dropwise. The mixture wasstirred for 5 minutes, at which time a voluminous yellow precipitate hadformed. The mixture was poured into water and the solids were collectedby filtration to afford dimethyl6-bromothiazolo[5,4-b]pyrazin-2-ylcarbonimidodithioate (680 mg, 67%yield) as a yellow solid of sufficient purity to use without furtherpurification. 1H NMR (400 MHz, CDCl₃) δ ppm 8.63 (s, 1H) 2.68 (s, 6H).

Step B:(R)—N-(6-bromothiazolo[5,4-b]pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

A mixture of dimethyl6-bromothiazolo[5,4-b]pyrazin-2-ylcarbonimidodithioate (300 mg, 0.895mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (210 mg,0.895 mmol) and cesium carbonate (600 mg, 1.79 mmol) in acetonitrile (25mL) was heated on a 100° C. oil bath for 2 hours in an open flask, withnitrogen bubbling through the solution the entire time to help in theremoval of methanethiol. After 2 hours, TLC showed the reaction to becomplete, so the mixture was cooled to ambient temperature, diluted withwater and concentrated in vacuo. The mixture was extracted withchloroform (4×). The combined organics were washed with brine, driedover sodium sulfate, filtered, concentrated in vacuo, and the cruderesidue was purified by silica gel chromatography (2-40% 9:1methanol:ammonium hydroxide-chloroform). The product fractions werecombined and concentrated in vacuo to afford(R)—N-(6-bromothiazolo[5,4-b]pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(200 mg, 57% yield). 1H NMR (400 MHz, CDCl₃) δ ppm 9.39 (br. s., 1H)8.48 (s, 1H) 4.05 (d, J=9.79 Hz, 1H) 3.72 (d, J=9.79 Hz, 1H) 3.42 (dd,J=15.06, 1.76 Hz, 1H) 2.73-3.08 (m, 5H) 2.10-2.22 (m, 2H) 1.73-1.84 (m,J=14.09, 9.94, 4.17, 4.17 Hz, 1H) 1.52-1.65 (m, 2H). MS (LC/MS)R.T.=1.29; [M+H]⁺=394.99.

Example 264(R)—N-(6-(methylthio)thiazolo[5,4-b]pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

A mixture of dimethyl6-bromothiazolo[5,4-b]pyrazin-2-ylcarbonimidodithioate from Step A ofExample 263 (100 mg, 0.298 mmol), (S)-3-(aminomethyl)quinuclidin-3-oldihydrochloride (68 mg, 0.298 mmol) and cesium carbonate (100 mg, 0.60mmol) in DMF (1.5 mL) was placed in a 1 dram vial and heated on a 100°C. oil bath for 1 hour, at which time, sodium thiomethoxide (100 mg,1.43 mmol) was added and the mixture was heated overnight. The mixturewas cooled to ambient temperature and poured into water (20 mL) and theresulting solids were collected by filtration and then purified bysilica gel chromatography (2-40% 9:1 methanol:ammoniumhydroxide-chloroform). The product fractions were combined andconcentrated in vacuo to afford(R)—N-(6-(methylthio)thiazolo[5,4-b]pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(52 mg, 46% yield). 1H NMR (500 MHz, CDCl₃) δ ppm 9.39 (br. s., 1H) 8.31(s, 1H) 4.03 (d, J=9.77 Hz, 1H) 3.70 (d, J=9.77 Hz, 1H) 3.41 (dd,J=14.95, 1.83 Hz, 1H) 2.73-3.10 (m, 5H) 2.63 (s, 3H) 2.10-2.25 (m, 2H)1.47-1.86 (m, 3H). MS (LC/MS) R.T.=1.04; [M+H]⁺=363.04.

Example 265(R)—N-(5-Methoxythiazolo[5,4-d]pyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 5-Methoxythiazolo[5,4-d]pyrimidin-2-amine

Ethyl 5-chlorothiazolo[5,4-d]pyrimidin-2-ylcarbamate (250 mg, 0.966mmol) was suspended in MeOH (10 mL) and a 25% (w/w) solution of sodiummethoxide in methanol was added (10 mL, 46.3 mmol). The resultingsolution was refluxed overnight, cooled to ambient temperature, pouredinto an equal volume of water and extracted with chloroform (4×). Asignificant amount of compound was still present in the aqueous phase,so this was concentrated to residue, and then dissolved in a smallamount of 1N HCl (not enough to make the resulting solution acidic) andextracted again with EtOAc (5×). The combined organics were washed withbrine, dried over sodium sulfate, filtered and concentrated in vacuo.5-Methoxythiazolo[5,4-d]pyrimidin-2-amine (144 mg, 0.790 mmol, 82%yield) was thus obtained as a white solid. 1H NMR (400 MHz, DMSO-d₆) δppm 8.43 (s, 1H) 7.81 (s, 2H) 3.90 (s, 3H). MS (LC/MS) R.T.=0.73;[M+H]⁺=183.03.

Step B: Dimethyl5-methoxythiazolo[5,4-d]pyrimidin-2-ylcarbonimidodithioate

To a suspension of 5-methoxythiazolo[5,4-d]pyrimidin-2-amine (911 mg,5.00 mmol) in DMF (5 mL) was added 20.0M sodium hydroxide (500 μL, 10.00mmol). The mixture was allowed to stir 10 min at room temperature atwhich time carbon disulfide was added (750 μL, 12.50 mmol) and theresulting reddish brown mixture was stirred for 10 minutes. Anadditional portion of 20.0M sodium hydroxide (500 μL, 10.00 mmol) wasadded and the mixture was again stirred for 10 minutes. Finally,iodomethane (750 μL, 12.00 mmol) was added dropwise. The mixture wasstirred for 5 minutes, at which time a voluminous yellow precipitate hadformed. The mixture was poured into water and the solids were collectedby filtration to afford a yellow solid that was further purified bysilica gel chromatography (2-20% EtOAc/CHCl₃) to provide dimethyl5-methoxythiazolo[5,4-d]pyrimidin-2-ylcarbonimidodithioate (380 mg, 27%yield). 1H NMR (400 MHz, CDCl₃) δ ppm 8.90 (s, 1H) 4.09 (s, 3H) 2.66 (s,6H).

Step C:(R)—N-(5-methoxythiazolo[5,4-d]pyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

A mixture of dimethyl5-methoxythiazolo[5,4-d]pyrimidin-2-ylcarbonimidodithioate (100 mg,0.349 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (80 mg,0.349 mmol) and cesium carbonate (228 mg, 0.698 mmol) in DMF (1.7 mL)was heated to 100° C. for 2 hours. The reaction mixture was cooled toambient temperature, poured into water and the solids were collected byfiltration to afford(R)—N-(5-methoxythiazolo[5,4-d]pyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(78 mg, 64% yield). 1H NMR (500 MHz, CDCl₃) δ ppm 9.12 (br. s., 1H) 8.63(s, 1H) 3.95-4.18 (m, 4H) 3.71 (d, J=9.77 Hz, 1H) 3.41 (d, J=15.26 Hz,1H) 2.74-3.10 (m, 5H) 2.11-2.27 (m, 2H) 1.71-1.86 (m, 1H) 1.50-1.70 (m,2H). MS (LC/MS) R.T.=1.66; [M+H]⁺=347.0.

Example 266(R)—N-(5-Ethyl-1,3,4-oxadiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: Dimethyl 5-ethyl-1,3,4-oxadiazol-2-ylcarbonimidodithioate

To a solution of 5-ethyl-1,3,4-oxadiazol-2-amine (2.26 g, 20 mmol) inDMF (10 ml) was added NaOH (20M, 2 ml), CS₂ (3 ml), NaOH (20M, 2 ml) andiodomethane (3 ml) slowly over 10 minutes. The mixture was stirred atroom temperature for 2 h and poured into 30 ml water. The precipitatedyellow solid was filtered off, washed with water, and dried to obtainthe desired product, dimethyl5-ethyl-1,3,4-oxadiazol-2-ylcarbonimidodithioate, a white solid (2.6 g,59.8%). ¹H NMR (500 MHz, CDCl3) δ ppm 2.86-2.83 (q, 2H), 2.63 (s, 6H),1.3901.35 (t, 3H).

MS (LCMS) [M+H]=217.95; R.T.=1.93 min.

Step B:(R)—N-(5-Ethyl-1,3,4-oxadiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

A mixture of dimethyl 5-ethyl-1,3,4-oxadiazol-2-ylcarbonimidodithioate(327 mg, 1.5 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride(235 mg, 1.5 mmol) and cesium carbonate (1000 mg, 3.16 mmol) in DMF (10ml) was stirred overnight at room temperature. The mixture wasconcentrated and purified on a Biotage silica gel column (100% ethylacetate, then 10-35% 9:1 methanol:ammonium hydroxide-chloroform) toobtain the desired product,(R)—N-(5-ethyl-1,3,4-oxadiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(290 mg, 66%). ¹H NMR (500 MHz, MeOD) δ ppm 4.05 (d, 1H), 3.74 (d, 1H),3.3-3.2 (d, 1H), 3.2-3.1 (d, 1H), 3.0-2.9 (m, 2H), 2.9-2.8 (m, 5H), 2.2(s, 1H), 2.15-2.0 (m, 1H), 1.9-1.6 (m, 3H), 1.4-1.3 (t, 3H). (m, 2H). MS(LCMS) [M+H]=278.09; R.T.=0.48 min.

Example 267(R)—N-(3,5-Dichloropyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 3,5-Dichloro-2-isothiocyanatopyridine

To 3,5-dichloropyridin-2-amine (0.36 g, 2.209 mmol) in dichloromethane(25 mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one (0.523 g, 2.253mmol). The reaction was stirred at 40° C. for 3 hours. The reaction wascooled to room temperature and the crude was purified by chromatography(Biotage: 25-100% ethyl acetate/hexane) to yield to yield3,5-dichloro-2-isothiocyanatopyridine (0.4 g, 1.951 mmol, 88% yield). 1HNMR (500 MHz, DMSO-D6) δ ppm 8.50 (t, J=2.59 Hz, 1H), 8.45 (t, J=2.59Hz, 1H). MS (LC/MS) R.T.=2.07; [M+H]⁺=204.8.

Step B:(R)—N-(3,5-Dichloropyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To 3,5-dichloro-2-isothiocyanatopyridine (0.11 g, 0.55 mmol) inN,N-dimethylformamide (10 mL) was added Et₃N (0.17 mL, 1.21 mmol) and(S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.13 g, 0.56 mmol)at room temperature. The reaction was stirred at 70° C. for 2 hours. Thereaction was cooled to room temperature and concentrated in vacuo. Thecrude urea was purified by chromatography (Biotage: 85% CHCl₃, 14% MeOH,1% NH₄OH). The product was then treated with N,N-dimethylformamide (10mL) and N,N′-diisopropylcarbodiimide (0.26 mL, 1.65 mmol). The reactionwas heated to 70° C. for 2 hours. The reaction was cooled to roomtemperature and concentrated in vacuo to yield the crude product. Thecrude product was purified by chromatography (Biotage: 85% CHCl₃, 14%MeOH, 1% NH₄OH) to yield(R)—N-(3,5-dichloropyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.08 g, 0.24 mmol, 44% yield) as a white powder. 1H NMR (500 MHz,DMSO-D6) 8 ppm 8.91 (s, 1H), 8.11-8.17 (m, 1H), 7.97 (d, J=2.44 Hz, 1H),3.84 (d, J=9.77 Hz, 1H), 3.59 (d, J=9.77 Hz, 1H), 2.95-3.04 (m, 2H),2.72-2.81 (m, 2H), 2.66 (t, J=7.63 Hz, 2H), 2.01 (s, 1H), 1.89 (s, 1H),1.54-1.62 (m, 2H), 1.42-1.50 (m, 1H). MS (LC/MS) R.T.=0.78; [M+]⁺=326.1.

Example 268(R)—N-(5-chlorothiazolo[5,4-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′bicyclo[2.2.2]octan]-2-amine

Step A: Dimethyl 5-chlorothiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate

To a suspension of 5-chlorothiazolo[5,4-b]pyridin-2-amine (930 mg, 5.00mmol) in DMF (5 mL) was added 20.0M sodium hydroxide (500 μL, 10.00mmol). The mixture was allowed to stir 10 min at room temperature atwhich time carbon disulfide was added (750 μL, 12.50 mmol) and themixture was stirred for 10 minutes. An additional portion of 20.0Msodium hydroxide (500 μL, 10.0 mmol) was added and the mixture was againstirred for 10 minutes. Finally, iodomethane (750 μL, 12.00 mmol) wasadded dropwise. An exotherm was noticed during this addition. Themixture was stirred for 15 minutes, at which time a voluminousprecipitate had formed. The mixture was poured into water and the solidswere collected by filtration. Most of the collected solids were paleyellow and crystalline. A few small clumps of a slightly darker gummyorange solid were also present, and these were manually removed anddiscarded. The remainder was the title compound, dimethyl5-chlorothiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate (1.00 g, 69%yield). 1H NMR (400 MHz, CDCl₃) δ ppm 8.04 (d, J=8.53 Hz, 1H) 7.38 (d,J=8.53 Hz, 1H) 2.66 (s, 6H).

Step B:(R)—N-(5-chlorothiazolo[5,4-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′bicyclo[2.2.2]octan]-2-amine

A mixture of dimethyl5-chlorothiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate (100 mg, 0.35mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (79 mg, 0.35mmol) and cesium carbonate (225 mg, 0.69 mmol) in DMF (1.7 mL) washeated to 100° C. for 2 hours. The reaction mixture was cooled toambient temperature, poured into water and the solids collected byfiltration. The crude solids were purified by silica gel chromatography(2-40% 9:1 methanol:ammonium hydroxide-chloroform) to afford(R)—N-(5-chlorothiazolo[5,4-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′bicyclo[2.2.2]octan]-2-amine (62 mg, 51% yield). 1H NMR (400 MHz,DMSO-d₆) δ ppm 9.13 (br. s., 1H) 7.93 (d, J=8.53 Hz, 1H) 7.45 (d, J=8.28Hz, 1H) 3.92 (d, J=10.29 Hz, 1H) 3.67 (d, J=10.29 Hz, 1H) 3.00-3.14 (m,2H) 2.77-2.93 (m, 2H) 2.69 (t, J=7.65 Hz, 2H) 2.12 (br. s., 1H) 1.95(br. s., 1H) 1.43-1.72 (m, 3H). MS (LC/MS) R.T.=1.10; [M+H]⁺=350.10.

Example 269 (R)—N⁵,N⁵-dimethyl-N²-(4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-yl)thiazolo[5,4-d]pyrimidine-2,5-diamine

Step A: Ethyl 5-chlorothiazolo[5,4-d]pyrimidin-2-ylcarbamate

Ethoxycarbonyl isothiocyanate (4.32 mL, 36.6 mmol) and2,4-dichloro-pyrimidin-5-ylamine (3.00 g, 18.29 mmol) were mixed neatand sonicated for 5 minutes to help dissolve. The mixture was stirred atambient temperature for 10 minutes, at which time the entire mixture hadsolidified. Methanol (100 mL) was added and the mixture was refluxed for30 minutes, cooled to ambient temperature and the solids were collectedby filtration to afford ethyl5-chlorothiazolo[5,4-d]pyrimidin-2-ylcarbamate (3.8 g, 80% yield). 1HNMR (400 MHz, DMSO-d₆) δ ppm 12.64 (s, 1H) 9.05 (s, 1H) 4.31 (q, J=7.19Hz, 2H) 1.32 (t, J=7.15 Hz, 3H).

Step B: Ethyl 5-(dimethylamino)thiazolo[5,4-d]pyrimidin-2-ylcarbamate

Ethyl 5-chlorothiazolo[5,4-d]pyrimidin-2-ylcarbamate (300 mg, 1.16 mmol)was suspended in a 2.0 M solution of dimethylamine in methanol (5.0 mL,10.00 mmol) in a pressure vessel, which was sealed and heated overnighton a 75° C. oil bath. The mixture was cooled to ambient temperature, thesolvent was evaporated and the residue was partitioned between aqueousbicarbonate and chloroform and extracted 3 times. The combined organicswere washed with brine, dried over sodium sulfate, filtered andconcentrated in vacuo to afford ethyl5-(dimethylamino)thiazolo[5,4-d]pyrimidin-2-ylcarbamate (236 mg, 99%yield). 1H NMR (400 MHz, DMSO-d₆) δ ppm 11.97 (s, 1H) 8.67 (s, 1H) 4.26(q, J=7.03 Hz, 2H) 3.17 (s, 6H) 1.16-1.40 (m, 3H). MS (LC/MS) R.T.=1.88;[M+H]⁺=268.09.

Step C: Ethyl N⁵,N⁵-dimethylthiazolo[5,4-d]pyrimidine-2,5-diamine

Ethyl 5-(dimethylamino)thiazolo[5,4-d]pyrimidin-2-ylcarbamate (236 mg,0.88 mmol) was suspended in a 25% (w/w) solution of sodium methoxide inmethanol (5 mL, 23.0 mmol) and the mixture was heated to refluxovernight. The reaction mixture was evaporated to dryness and theresidue was partitioned between water and chloroform and extracted 3times. The combined organics were washed with brine, dried over sodiumsulfate, filtered and concentrated in vacuo to afford ethylN⁵,N⁵-dimethylthiazolo[5,4-d]pyrimidine-2,5-diamine (170 mg, 99% yield)as a white solid. 1H NMR (400 MHz, DMSO-d₆) δ ppm 8.27 (s, 1H) 7.44 (s,2H) 3.10 (s, 6H).

Step D: Dimethyl5-(dimethylamino)thiazolo[5,4-d]pyrimidin-2-ylcarbonimidodithioate

To a suspension of ethylN⁵,N⁵-dimethylthiazolo[5,4-d]pyrimidine-2,5-diamine (160 mg, 0.819 mmol)in DMF (1 mL) was added 20.0 M sodium hydroxide (100 μL, 2.00 mmol). Themixture was allowed to stir 10 min at room temperature at which timecarbon disulfide was added (120 μL, 2 mmol) and the resulting reddishbrown mixture was stirred for 10 minutes. An additional portion of 20.0M sodium hydroxide (100 μL, 2.0 mmol) was added and the mixture wasagain stirred for 10 minutes. Finally, iodomethane (120 μL, 1.9 mmol)was added dropwise. The mixture was stirred for 5 minutes, at which timea voluminous yellow precipitate had formed. The mixture was poured intowater and the solids were collected by filtration to afford dimethyl5-(dimethylamino)thiazolo[5,4-d]pyrimidin-2-ylcarbonimidodithioate (194mg, 79% yield). 1H NMR (400 MHz, CDCl₃) δ ppm 8.75 (s, 1H) 3.26 (s, 6H)2.64 (s, 6H).

Step E:(R)—N⁵,N⁵-dimethyl-N²-(4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]-2-yl)thiazolo[5,4-d]pyrimidine-2,5-diamine

A mixture of dimethyl5-(dimethylamino)thiazolo[5,4-d]pyrimidin-2-ylcarbonimidodithioate (90mg, 0.301 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (83mg, 0.361 mmol) and cesium carbonate (196 mg, 0.60 mmol) in DMF (1.0 mL)was heated to 100° C. for 1.5 hours. The reaction mixture was cooled toambient temperature, poured into water and extracted with chloroform(4×). The combined organics were washed with brine, dried over sodiumsulfate, filtered, concentrated in vacuo, and the crude residue waspurified by silica gel chromatography (2-40% 9:1 methanol:ammoniumhydroxide-chloroform) to afford(R)—N⁵,N⁵-dimethyl-N²-(4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]-2-yl)thiazolo[5,4-d]pyrimidine-2,5-diamine(81 mg, 71% yield) as a tan solid. 1H NMR (400 MHz, CDCl₃) δ ppm 9.07(br. s., 1H) 8.50 (s, 1H) 4.01 (d, J=9.54 Hz, 1H) 3.67 (d, J=9.54 Hz,1H) 3.39 (dd, J=14.93, 1.63 Hz, 1H) 3.23 (s, 6H) 2.71-3.10 (m, 5H)2.10-2.24 (m, 2H) 1.68-1.84 (m, 1H) 1.46-1.68 (m, 2H). MS (LC/MS)R.T.=0.87; [M+H]⁺=360.23.

Example 270(R)—N-([1,2,4]Triazol[1,5-a]pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: [1,2,4]Triazolo[1,5-a]pyrazin-2-amine

To a solution of pyrazin-2-amine (25 g, 260 mmol) in dioxane (300 ml) atroom temperature was added ethoxycarbonyl-isothiocyanate (37.9 g, 289mmol) slowly. The mixture was stirred for 18 hours and the solvent wasevaporated under vacuum. The residual solid was dissolved in a mixtureof methanol (150 ml) and ethanol (150 ml). To this solution was addedTEA (109 ml, 780 mmol) and hydroxylamine hydrochloride (72.5 g, 1040mmol). The mixture was stirred at room temperature for 2 hours and washeated to reflux for 4 hours. The crude mixture was cooled to roomtemperature and the solvent was evaporated. The residual solid waspurified by column chromatography (0-20% methanol/CH₂Cl₂) to obtain awhite solid (60 g). The solid was taken into EtOAc and water. Theaqueous layer was extracted with EtOAc twice. The combined organic layerwas washed with brine and dried over sodium sulfate to obtain[1,2,4]triazolo[1,5-a]pyrazin-2-amine as a white solid (12 g, 88 mmol,33%). MS (LCMS) [M+H]=135.96; R.T.=0.21 min.

Step B: Dimethyl[1,2,4]triazol[1,5-a]pyrazin-2-ylcarbonimidodithioate

To a solution of [1,2,4]triazolo[1,5-a]pyrazin-2-amine (676 mg, 5 mmol)in DMF (10 ml) was added NaOH (20 M, 0.5 ml), CS₂ (1 ml), NaOH (20 M,0.5 ml) and iodomethane (1 ml) slowly over 10 minutes. The mixture wasstirred at room temperature for 1 h and 10 ml water was added to thereaction mixture, which became cloudy. The mixture was extracted withEtOAc (100 ml×3). The combined organic layers were washed with brine,dried over sodium sulfate, filtered, and evaporated. The residue waspurified on a Biotage silica gel column (ethyl acetate-hexane 10-30%) toobtain dimethyl[1,2,4]triazol[1,5-a]pyrazin-2-ylcarbonimidodithioate asa yellow solid (720 mg, 3 mmol, 60%). ¹H NMR (500 MHz, CDCl3) δ ppm 9.2(2, 1H), 8.5 (d, 1H), 8.2 (d, 1H), 2.67 (s, 6H). MS (LCMS) [M+H]=239.92.[M+Na]=261.89; R.T.=1.55 min.

Step C:(R)—N-([1,2,4]Triazol[1,5-a]pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

A mixture ofdimethyl[1,2,4]triazol[1,5-a]pyrazin-2-ylcarbonimidodithioate (120 mg,0.50 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (120 mg,0.76 mmol) and cesium carbonate (492 mg, 1.5 mmol) in DMF (5 ml) washeated at 70° C. for 6 hours. The mixture was concentrated and purifiedon a Biotage silica gel column (100% ethyl acetate, then 10-35% 9:1methanol:ammonium hydroxide-chloroform) to obtain the desired product,(R)—N-([1,2,4]triazol[1,5-a]pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(85 mg, 26.7%) as a white solid. ¹H NMR (500 MHz, MeOD) δ ppm 9.0 (m,1H), 8.71-8.70 (m, 1H), 8.15-8.10 (m, 1H), 4.15-4.0 (d, 1H), 3.85-3.8(d, 1H), 3.6-3.5 (d, 1H), 3.4-3.3 (d, 1H), 3.3-3.0 (m, 4H), 2.4-2.2 (m,2H), 2.0-1.8 (m, 3H).

MS (LCMS) [M+H]=300.06; R.T.=0.2 min.

Example 271(R)—N-(Thiazolo[5,4-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: Dimethyl thiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate

To a suspension of thiazolo[5,4-b]pyridin-2-amine (300 mg, 1.98 mmol) inDMF (2 mL) was added 20.0M sodium hydroxide (200 μL, 4.0 mmol). Themixture was allowed to stir 10 min at room temperature at which timecarbon disulfide was added (300 μL, 4.96 mmol) and the resulting reddishbrown mixture was stirred for 10 minutes. An additional portion of 20.0Msodium hydroxide (200 μL, 4.0 mmol) was added and the mixture was againstirred for 10 minutes. Finally, iodomethane (300 μL, 4.76 mmol) wasadded dropwise. The mixture was stirred for 5 minutes, at which time avoluminous yellow precipitate had formed. The mixture was poured intowater and the solids were collected by filtration to afford dimethylthiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate (190 mg, 38% yield) as ayellow solid of sufficient purity to use without further purification.1H NMR (500 MHz, CDCl₃) 8 ppm 8.47 (d, J=4.58 Hz, 1H) 8.11 (dd, J=8.24,1.53 Hz, 1H) 7.37 (dd, J=8.24, 4.88 Hz, 1H) 2.66 (s, 6H).

Step B:(R)—N-(Thiazolo[5,4-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

A mixture of dimethyl thiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate(90 mg, 0.35 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride(97 mg, 0.42 mmol) and cesium carbonate (230 mg, 0.71 mmol) in DMF (1mL) was heated to 100° C. for 2 hours. The reaction mixture was cooledto ambient temperature, poured into water and extracted with chloroform(4×). The combined organics were washed with brine, dried over sodiumsulfate, filtered and concentrated in vacuo. The mixture was purified bysilica gel chromatography (2-40% 9:1 methanol:ammoniumhydroxide-chloroform). The product fractions were combined andconcentrated in vacuo to afford(R)—N-(thiazolo[5,4-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(84 mg, 76% yield). 1H NMR (400 MHz, CDCl₃) 8 ppm 9.30 (br. s., 1H) 8.37(dd, J=4.77, 1.51 Hz, 1H) 7.82 (dd, J=8.03, 1.51 Hz, 1H) 7.28 (dd,J=8.03, 4.77 Hz, 1H) 4.05 (d, J=9.54 Hz, 1H) 3.70 (d, J=9.54 Hz, 1H)3.42 (dd, J=15.06, 1.76 Hz, 1H) 2.75-3.07 (m, 5H) 2.14-2.26 (m, 2H)1.71-1.84 (m, J=13.99, 9.79, 4.17, 4.17 Hz, 1H) 1.48-1.68 (m, 2H). MS(LC/MS) R.T.=0.64; [M+H]⁺=316.15.

Example 272(R)—N-(Thiazolo[5,4-b]pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(6-Bromothiazolo[5,4-b]pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(44 mg, 0.111 mmol) was suspended in MeOH (50 mL) and 3N HCl was addeduntil all solids had dissolved (˜10 ml). The reaction flask was flushedwith nitrogen and then 10% palladium on carbon (35 mg) was added, andthe flask was fitted with a hydrogen balloon. The mixture was allowed toreact overnight, at which time TLC showed consumption of the startingmaterial. The flask was flushed with nitrogen, filtered through celiteand washed with methanol. The combined filtrates were concentrated by˜90% to remove most of the methanol, and the solution was made basic bythe addition of a saturated solution of sodium bicarbonate. The basicaqueous phase was extracted with chloroform (4×). The combined organicswere washed with brine, dried over sodium sulfate, filtered andconcentrated in vacuo. The mixture was purified by silica gelchromatography (2-40% [9:1 methanol:ammonium hydroxide]-chloroform). Theproduct fractions were combined and concentrated in vacuo to afford(R)—N-(thiazolo[5,4-b]pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(24 mg, 0.075 mmol, 67.5% yield). 1H NMR (400 MHz, CDCl₃) δ ppm 9.50(br. s., 1H) 8.41 (d, J=2.76 Hz, 1H) 8.27 (d, J=2.76 Hz, 1H) 4.06 (d,J=9.79 Hz, 1H) 3.72 (d, J=9.79 Hz, 1H) 3.43 (dd, J=15.06, 1.76 Hz, 1H)2.74-3.09 (m, 5H) 2.12-2.25 (m, 2H) 1.71-1.86 (m, 1H) 1.49-1.67 (m, 2H).MS (LC/MS) R.T.=0.75; [M+H]⁺=317.13.

Example 273(R)—N-(7-Methoxy-5-methylthiazolo[5,4-d]pyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: Ethyl 7-chloro-5-methylthiazolo[5,4-d]pyrimidin-2-ylcarbamate

To a mixture of 4,6-dichloro-2-methylpyrimidin-5-amine (1 g, 5.62 mmol)and O-ethyl carbonisothiocyanatidate (0.66 mL, 5.62 mmol) was addedtoluene (2 mL) to wet the solids completely. The mixture was placed on100° C. oil bath for 1.5 hours, at which time, the mixture had seized togive a solid mass. The solids were cooled to ambient temperature andtriturated with ether, then the resulting solids were collected byfiltration to give ethyl7-chloro-5-methylthiazolo[5,4-d]pyrimidin-2-ylcarbamate (1.08 g, 3.96mmol, 70.5% yield). 1H NMR (400 MHz, DMSO-d₆) δ ppm 12.70 (br. s., 1H)4.30 (q, J=7.19 Hz, 2H) 2.69 (s, 3H) 1.30 (t, J=7.15 Hz, 3H).

Step B: 7-Methoxy-5-methylthiazolo[5,4-d]pyrimidin-2-amine

Ethyl 7-chloro-5-methylthiazolo[5,4-d]pyrimidin-2-ylcarbamate (300 mg,1.100 mmol) was suspended in a 25% w/w solution of sodium methoxide inmethanol (5 mL, 23.14 mmol) and the mixture was refluxed overnight. Themixture was cooled to ambient temperature, diluted with water andextracted with chloroform (4×). The combined organics were washed withbrine, dried over sodium sulfate, filtered and concentrated in vacuo toafford 7-methoxy-5-methylthiazolo[5,4-d]pyrimidin-2-amine (120 mg, 0.612mmol, 55.6% yield). 1H NMR (400 MHz, DMSO-d₆) δ ppm 7.71 (s, 2H) 3.98(s, 3H) 2.52 (s, 3H).

Step C: Dimethyl7-methoxy-5-methylthiazolo[5,4-d]pyrimidin-2-ylcarbonimidodithioate

To a suspension of 7-methoxy-5-methylthiazolo[5,4-d]pyrimidin-2-amine(100 mg, 0.51 mmol) in DMF (0.5 mL) was added 16.0M sodium hydroxide (75μL, 1.2 mmol). The mixture was allowed to stir 10 min at roomtemperature at which time carbon disulfide was added (80 μL, 1.27 mmol)and the resulting reddish brown mixture was stirred for 10 minutes. Anadditional portion of 16.0M sodium hydroxide (75 μL, 1.2 mmol) was addedand the mixture was again stirred for 10 minutes. Finally, iodomethane(80 μL, 1.29 mmol) was added dropwise. The mixture was stirred for 5minutes, at which time a voluminous yellow precipitate had formed. Themixture was poured into water and the solids were collected byfiltration to afford a crude yellow solid that was further purified bysilica gel chromatography (2-20% ethyl acetate-chloroform). The productfractions were combined and concentrated in vacuo to afford dimethyl7-methoxy-5-methylthiazolo[5,4-d]pyrimidin-2-ylcarbonimidodithioate (90mg, 59% yield) as a yellow solid. 1H NMR (400 MHz, CDCl₃) δ ppm 4.17 (s,3H) 2.71 (s, 3H) 2.64 (s, 6H).

Step D:(R)—N-(7-Methoxy-5-methylthiazolo[5,4-d]pyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

A mixture of dimethyl7-methoxy-5-methylthiazolo[5,4-d]pyrimidin-2-ylcarbonimidodithioate (56mg, 0.19 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (51mg, 0.22 mmol) and cesium carbonate (175 mg, 0.54 mmol) in DMF (0.5 mL)was heated to 100° C. for 2 hours. The reaction mixture was cooled toambient temperature, poured into water and extracted with chloroform(4×). The combined organics were washed with brine, dried over sodiumsulfate, filtered and concentrated in vacuo. The mixture was purified bysilica gel chromatography (2-40% [9:1 methanol:ammoniumhydroxide]-chloroform). The product fractions were combined andconcentrated in vacuo to afford(R)—N-(7-methoxy-5-methylthiazolo[5,4-d]pyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(34 mg, 50% yield). 1H NMR (400 MHz, CDCl₃) 8 ppm 9.10 (br. s., 1H) 4.14(s, 3H) 4.03 (d, J=9.54 Hz, 1H) 3.68 (d, J=9.54 Hz, 1H) 3.39 (dd,J=14.93, 1.63 Hz, 1H) 2.74-3.07 (m, 5H) 2.68 (s, 3H) 2.04-2.28 (m, 2H)1.70-1.86 (m, 1H) 1.44-1.67 (m, 2H). MS (LC/MS) R.T.=1.10;[M+H]⁺=361.32.

Example 274(R)—N-(7-Methoxythiazolo[5,4-d]pyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: Dimethyl7-methoxy-5-methylthiazolo[5,4-d]pyrimidin-2-ylcarbonimidodithioate

To a suspension of 7-methoxythiazolo[5,4-d]pyrimidin-2-amine (300 mg,1.67 mmol) in DMF (1.5 mL) was added 16.0M sodium hydroxide (210 μL, 3.4mmol). The mixture was allowed to stir 10 min at room temperature atwhich time carbon disulfide was added (250 μL, 4.15 mmol) and theresulting reddish brown mixture was stirred for 10 minutes. Anadditional portion of 16.0M sodium hydroxide (210 μL, 3.4 mmol) wasadded and the mixture was again stirred for 10 minutes. Finally,iodomethane (250 μL, 4.00 mmol) was added dropwise. The mixture wasstirred for 10 minutes, at which time a voluminous yellow precipitatehad formed. The mixture was poured into water and the solids werecollected by filtration to afford dimethyl7-methoxy-5-methylthiazolo[5,4-d]pyrimidin-2-ylcarbonimidodithioate (324mg, 69% yield) as a yellow solid. 1H NMR (400 MHz, CDCl₃) δ ppm 8.60 (s,1H) 4.20 (s, 3H) 2.65 (s, 6H).

Step B:(R)—N-(7-Methoxythiazolo[5,4-d]pyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

A mixture of dimethyl7-methoxythiazolo[5,4-d]pyrimidin-2-ylcarbonimidodithioate (150 mg, 0.52mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (132 mg, 0.58mmol) and cesium carbonate (427 mg, 1.31 mmol) in DMF (3 mL) was heatedto 100° C. for 2 hours. The reaction mixture was cooled to ambienttemperature, poured into water and extracted with chloroform (4×). Thecombined organics were washed with brine, dried over sodium sulfate,filtered and concentrated in vacuo. The mixture was purified by silicagel chromatography (2-40% [9:1 methanol:ammonium hydroxide]-chloroform).The product fractions were combined and concentrated in vacuo to afford(R)—N-(7-methoxythiazolo[5,4-d]pyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(95 mg, 51% yield). 1H NMR (400 MHz, CDCl₃) δ ppm 9.12 (br. s., 1H) 8.52(s, 1H) 4.16 (s, 3H) 4.05 (d, J=9.54 Hz, 1H) 3.70 (d, J=9.54 Hz, 1H)3.40 (dd, J=14.93, 1.88 Hz, 1H) 2.70-3.07 (m, 5H) 2.08-2.27 (m, 2H)1.68-1.85 (m, 1H) 1.48-1.66 (m, 2H). MS (LC/MS) R.T.=0.90;[M+H]⁺=347.34.

Example 275(R)-2-(4H-1′-Azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-ylamino)thiazole-5-carbonitrile

(R)-2-(4H-1′-Azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-ylamino)thiazole-5-carbonitrilewas synthesized by the method of Example 274, starting from2-amino-5-cyanothiazole. 1H NMR (500 MHz, DMSO-D6) δ ppm 9.05 (s, 1H),8.13 (s, 1H), 3.86 (d, J=10.38 Hz, 1H), 3.61 (d, J=10.38 Hz, 1H),3.01-3.10 (m, 2H), 2.83 (t, J=7.63 Hz, 2H), 2.62-2.71 (m, 2H), 2.09 (s,1H), 1.90-1.97 (m, 2H), 1.54-1.62 (m, 3H). MS (LC/MS) R.T.=0.52;[M+H]⁺=290.0.

Example 276(R)—N-(7-Bromopyrrolo[1,2-fl][1,2,4]triazin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(7-bromopyrrolo[1,2-f][1,2,4]triazin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas synthesized by the method of Example 274 starting from7-bromopyrrolo[1,2-f][1,2,4]triazin-4-amine. 1H NMR (400 MHz, MeOD) δppm 8.13 (1H, s), 7.04 (1H, d, J=4.53 Hz), 6.77 (1H, d, J=4.53 Hz), 4.09(1H, d, J=10.32 Hz), 3.79 (1H, d, J=10.58 Hz), 3.24 (1H, d), 3.12 (1H,d), 2.70-3.00 (4H, m), 2.06-2.25 (2H, m), 1.52-1.86 (3H, m) MS (LC/MS)R.T.=1.62; [M+H]⁺=377.2.

Example 277(R)—N-(1,6-Naphthyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(1,6-Naphthyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas synthesized by the method of Example 274 starting from1,6-naphthyridin-2-amine. 1H NMR (400 MHz, MeOD) δ ppm 8.99 (1H, s),8.48 (1H, d, J=6.04 Hz), 8.20 (1H, d, J=8.56 Hz), 7.77 (1H, d, J=6.04Hz), 7.12 (1H, d, J=8.81 Hz), 4.12 (1H, d, J=10.32 Hz), 3.82 (1H, d,J=10.32 Hz), 3.36 (1H, d), 3.21 (1H, d), 2.79-3.09 (4H, m), 2.08-2.30(2H, m), 1.56-1.95 (3H, m).

(LC/MS) R.T.=0.38; [M+H]⁺=310.3.

Example 278(R)—N-(Quinazolin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(Quinazolin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas synthesized by the method of Example 274 starting from2-aminoquinazoline. ¹H NMR (400 MHz, MeOD) δ ppm 9.27 (1H, s), 7.72-7.99(3H, m), 7.47 (1H, dd, J=7.55, 3.78 Hz), 4.07 (1H, d, J=10.07 Hz), 3.76(1H, d, J=10.07 Hz), 3.26 (1H, br. s.), 3.13 (1H, d), 2.70-3.03 (4H, m),2.17 (2H, br. s.), 1.50-1.88 (3H, m). (LC/MS) R.T.=1.11; [M+H]⁺=310.3.

Example 279(R)—N-(6,8-Dichloroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: N-(2,4-Dichlorobenzyl)-2,2-diethoxyacetimidamide

(2,4-Dichlorophenyl)methanamine (2 g, 11.4 mmol) was added to a solutionof methyl 2,2-diethoxyacetimidate (2.04 g, 12.6 mmol) in methanol (10ml). The mixture was heated at 70° C. for 1 h. The mixture was purifiedby chromatography (Biotage: 100% ethyl acetate). The desired fractionswere concentrated to yieldN-(2,4-dichlorobenzyl)-2,2-diethoxyacetimidamide (2.8 g, 9.2 mmol, 72.7%yield) as a colorless viscous oil. 1H NMR (500 MHz, DMSO-D₆) δ ppm7.27-7.70 (m, 3H), 4.77 (s, 1H), 4.14-4.35 (m, 2H), 3.45-3.68 (m, 4H),1.09-1.29 (m, 6H). LC/MS RT=2.03; [M+H]⁺=304.9.

Step B: 6,8-Dichloroisoquinolin-3-amine

To sulfuric acid (4 mL, 75 mmol) was addedN-(2,4-dichlorobenzyl)-2,2-diethoxyacetimidamide (2 g, 6.6 mmol) at roomtemperature. The reaction was heated to 40° C. for 18 hours. TLC andLC/MS indicated the presence of product. The reaction was cooled to roomtemperature and quenched with aq. NaOH (˜15 M) until the reactionmixture was ˜pH 7. The crude product was extracted with ethyl acetate(2×50 mL) and the organics were dried with MgSO₄, filtered, andconcentrated in vacuo to yield the product. The crude product waspurified by chromatography (Biotage:10-80% ethyl acetate/hexanes) toyield 5,7-dichloroisoquinolin-1-amine (0.32 g, 1.50 mmol, 22.9% yield)as a dark yellow powder. 1H NMR (400 MHz, DMSO-D₆) δ ppm 8.99 (s, 1H),7.64-7.73 (m, 1H), 7.30 (d, J=2.01 Hz, 1H), 6.61 (s, 1H), 6.43 (s, 2H).MS (LC/MS) R.T.=1.40; [M+H]⁺=213.1.

Step C: 6,8-Dichloro-3-isothiocyanatoisoquinoline

To 6,8-dichloroisoquinolin-3-amine (0.27 g, 1.28 mmol) indichloromethane (20 mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one(0.30 g, 1.29 mmol) and the reaction mixture was stirred at 40° C. for 4hours. The reaction was cooled to room temperature and chromatographed(Biotage: 10-100% ethyl acetate/hexanes) to yield6,8-dichloro-3-isothiocyanatoisoquinoline (0.2 g, 0.78 mmol, 61.9%yield) as a powder. 1H NMR (500 MHz, DMSO-D₆) δ ppm 9.42 (s, 1H), 8.16(d, J=1.83 Hz, 1H), 8.02 (d, J=2.14 Hz, 1H), 7.92 (s, 1H). MS (LC/MS)R.T.=3.63; [M+H]⁺=255.0.

Step D:(R)—N-(6,8-Dichloroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To 6,8-dichloro-3-isothiocyanatoisoquinoline (0.17 g, 0.67 mmol) in DMF(10 mL) was added cesium carbonate (0.543 g, 1.67 mmol) and(S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.15 g, 0.67 mmol)at room temperature. The reaction was stirred at 70° C. for 2 hours. Thereaction was cooled to room temperature and concentrated in vacuo. Theproduct was treated with N,N′-diisopropylcarbodiimide (0.31 mL, 2.0mmol). The reaction was heated to 90° C. for 4 hours. The reaction wascooled to room temperature and concentrated to yield the crude product.The crude product was purified by chromatography (Biotage: 85% CHCl₃,14% MeOH, 1% NH₄OH). The product was taken up in a small amount of ethylacetate, which resulted in the formation of a precipate. It was filteredoff, washed with a small amount of ethyl acetate, and dried in a vacuumoven to yield(R)—N-(6,8-dichloroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.094 g, 0.24 mmol, 36.6% yield) as a white powder. 1H NMR (400 MHz,DMSO-D₆) δ ppm 9.23 (s, 1H), 8.71-8.83 (m, 1H), 7.90-8.00 (m, 1H),7.57-7.67 (m, 1H), 7.13-7.24 (m, 1H), 3.79-3.90 (m, 1H), 3.53-3.64 (m,1H), 2.93-3.04 (m, 2H), 2.72-2.82 (m, 2H), 2.61-2.70 (m, 2H), 1.99 (s,1H), 1.90 (s, 1H), 1.59 (d, J=4.78 Hz, 2H), 1.40-1.50 (m, 1K. MS (LC/MS)R.T.=1.68; [M+H]⁺=377.1.

Example 280

(R)—N-(6,7-Dichloroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: N-(3,4-Dichlorobenzyl)-2,2-diethoxyacetimidamide

(3,4-Dichlorophenyl)methanamine (2 g, 11.4 mmol) was added to a solutionof methyl 2,2-diethoxyacetimidate (2.04 g, 12.6 mmol) in methanol (10ml). The mixture was heated at 70° C. for 1 h. The mixture was purifiedby chromatography (Biotage: 100% ethyl acetate). The desired fractionswere concentrated to yieldN-(3,4-dichlorobenzyl)-2,2-diethoxyacetimidamide (2.8 g, 9.2 mmol, 72.7%yield) as a colorless viscous oil. 1H NMR (500 MHz, CDCl₃) δ ppm 7.45(m, 1H), 7.40 (m, 1H), 7.19 (dd, J=8.09, 1.98 Hz, 1H), 4.94 (s, 1H),4.43 (s, 2H), 3.47-3.77 (m, 4H), 1.41-1.79 (m, 6H). LC/MS RT=2.15;[M+H]⁺=305.1.

Step B: 6,7-Dichloroisoquinolin-3-amine and5,6-dichloroisoquinolin-3-amine

To sulfuric acid (4 mL, 75 mmol) was addedN-(3,4-dichlorobenzyl)-2,2-diethoxyacetimidamide (2 g, 6.6 mmol) at roomtemperature. The reaction was heated to 40° C. for 49 hours. TLC andLC/MS indicated the presence of product. The reaction was cooled to roomtemperature and quenched with aq. NaOH (˜15 M) until the reactionmixture was ˜pH 7. The crude product was extracted with ethyl acetate(2×50 mL) and the organics were dried with MgSO₄, filtered, andconcentrated in vacuo to yield the product. The crude product waspurified by chromatography (Biotage: 100% ethyl acetate to [90/10% ethylacetate/MeOH]) to yield approximately a 1:1 mixture of regioisomers6,7-dichloroisoquinolin-1-amine and 5,6-dichloroisoquinolin-3-amine (1.2g, 5.64 mmol, 86.0% yield) as a dark yellow powder. The regioisomerswere carried on without separation. 1H NMR: 1H NMR (500 MHz, DMSO-D₆) δppm 8.90 (s, 1H), 8.83 (s, 1H), 8.12 (s, 1H), 7.89 (s, 1H), 7.84 (d,J=8.54 Hz, 1H), 7.28 (d, J=8.85 Hz, 1H), 6.83 (s, 1H), 6.58 (s, 1H),6.48 (s, 2H), 6.25 (s, 2H). MS (LC/MS) R.T.=1.59; [M+H]⁺=213.0.

Step C: 6,7-Dichloro-3-isothiocyanatoisoquinoline and5,6-dichloro-3-isothiocyanatoisoquinoline

To 6,7-dichloroisoquinolin-3-amine and 5,6-dichloroisoquinolin-3-amine(0.410 g, 1.924 mmol) in dichloromethane (20 mL) was added1,1′-thiocarbonyldipyridin-2(1H)-one (0.469 g, 2.021 mmol) and thereaction mixture was stirred at 40° C. for 4 hours. The reaction wascooled to room temperature and chromatographed (Biotage: 10-100% ethylacetate/hexanes) to yield the separated regioisomers,6,7-dichloro-3-isothiocyanatoisoquinoline (0.2 g, 0.784 mmol, 40.7%yield) and 5,6-dichloro-3-isothiocyanatoisoquinoline (0.23 g, 0.902mmol, 46.8% yield) as yellow solids.5,6-dichloro-3-isothiocyanatoisoquinoline: 1H NMR (500 MHz, CDCl₃) δ ppm9.10 (s, 1H), 7.87 (d, J=8.85 Hz, 1H), 7.82 (s, 1H), 7.66 (d, J=8.55 Hz,1H). MS (LC/MS) R.T.=3.63; [M+H]⁺=255.0.6,7-dichloro-3-isothiocyanatoisoquinoline: 1H NMR (500 MHz, CDCl₃) δ ppm9.04 (s, 1H), 8.11 (s, 1H), 7.94 (s, 1H), 7.37 (s, 1H). MS (LC/MS)R.T.=3.42; [M+H]⁺=255.0.

Step C:(R)—N-(6,7-Dichloroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To 6,7-dichloro-3-isothiocyanatoisoquinoline (0.13 g, 0.510 mmol) in DMF(10 mL) was added cesium carbonate (0.42 g, 1.27 mmol) and(S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.118 g, 0.515mmol) at room temperature. The reaction was stirred at 70° C. for 2hours. The reaction was cooled to room temperature and concentrated invacuo. The crude urea was purified by chromatography (Biotage: 85%CHCl₃, 14% MeOH, 1% NH₄OH). The product was then treated with DMF (10mL) and N,N′-diisopropylcarbodiimide (0.238 mL, 1.529 mmol). Thereaction was heated to 90° C. for 18 hours. The reaction was cooled toroom temperature and concentrated to yield the crude product, which waspurified by chromatography (Biotage: 85% CHCl₃, 14% MeOH, 1% NH₄OH) toyield(R)—N-(6,7-dichloroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.12 g, 0.312 mmol, 61.2% yield). 1H NMR (500 MHz, CDCl₃) δ ppm 9.03(s, 1H), 8.87 (s, 1H), 7.96 (s, 1H), 7.83 (s, 1H), 7.24 (s, 1H),3.88-4.06 (m, 1H), 3.60-3.74 (m, 1H), 3.42 (d, J=14.65 Hz, 1H),2.82-3.15 (m, 5H), 2.23-2.34 (m, 1H), 2.18 (s, 1H), 1.72-1.87 (m, 1H),1.48-1.70 (m, 2H). MS (LC/MS) R.T.=1.63; [M+H]⁺=377.1.

Example 281(R)—N-(5,6-Dichloroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To 5,6-dichloro-3-isothiocyanatoisoquinoline (0.11 g, 0.431 mmol) in DMF(10 mL) was added cesium carbonate (0.351 g, 1.078 mmol) and(S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.100 g, 0.435mmol) at room temperature. The reaction was stirred at 70° C. for 2hours. The reaction was cooled to room temperature and concentrated invacuo. The crude urea was purified by chromatography (Biotage: 85%CHCl₃, 14% MeOH, 1% NH₄OH). The product was then treated with DMF (10mL) and N,N′-diisopropylcarbodiimide (0.202 mL, 1.293 mmol). Thereaction was heated to 90° C. for 18 hours. The reaction was cooled toroom temperature and concentrated to yield the crude product. The crudeproduct was purified by chromatography (Biotage: 85% CHCl₃, 14% MeOH, 1%NH₄OH) to yield(R)—N-(5,6-dichloroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.084 g, 0.218 mmol, 50.6% yield) as a yellow powder. 1H NMR (500 MHz,CDCl₃) δ ppm 9.09 (s, 1H), 8.93 (s, 1H), 7.63-7.82 (m, 2H), 7.40 (d,J=8.55 Hz, 1H), 3.99 (d, J=9.16 Hz, 1H), 3.78 (d, J=8.85 Hz, 1H), 3.51(d, J=14.65 Hz, 1H), 3.30 (d, J=14.65 Hz, 1H), 2.90-3.23 (m, 4H),2.33-2.48 (m, 1H), 2.29 (s, 1H), 1.83-1.94 (m, 1H), 1.62-1.83 (m,J=42.12 Hz, 2H).

MS (LC/MS) R.T.=1.57; [M+H]⁺=377.1.

Example 282(R)—N-(3,4-Dichloropyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(3,4-Dichloropyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by the method of Example 267, starting from2-amino-3,4-dichloropyridine. 1H NMR (500 MHz, DMSO-D₆) δ ppm 9.10 (s,1H), 8.08 (d, J=5.49 Hz, 1H), 7.13 (d, J=5.49 Hz, 1H), 3.86 (d, J=9.77Hz, 1H), 3.60 (d, J=9.77 Hz, 1H), 2.96-3.05 (m, 2H), 2.77 (t, J=7.63 Hz,2H), 2.66 (t, J=7.78 Hz, 2H), 1.97-2.05 (m, 1H), 1.86-1.94 (m, 1H),1.54-1.63 (m, 2H), 1.43-1.51 (m, 1H). MS (LC/MS) R.T.=0.78;[M+H]⁺=327.0.

Example 283(R)—N-(3-Chloropyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(3-Chloropyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by the method of Example 267, starting from2-amino-3-chloropyridine. 1H NMR (500 MHz, DMSO-D₆) δ ppm 9.06 (s, 1H),8.14-8.19 (m, 1H), 7.74-7.79 (m, J=7.78, 1.83, 1.83, 1.68 Hz, 1H),6.86-6.91 (m, 1H), 3.81-3.89 (m, 1H), 3.55-3.63 (m, 1H), 2.96-3.04 (m,2H), 2.78 (t, J=7.63 Hz, 2H), 2.67 (t, J=7.63 Hz, 2H), 1.96-2.02 (m,1H), 1.86-1.92 (m, J=5.65, 3.20 Hz, 1H), 1.54-1.63 (m, J=6.87, 3.66,3.51 Hz, 2H), 1.42-1.49 (m, 1H). MS (LC/MS) R.T.=0.26; [M+H]⁺=293.0.

Example 284(R)—N-(5-Chloro-3-fluoropyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(5-Chloro-3-fluoropyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by the method of Example 267, starting from2-amino-3-fluoro-5-chloropyridine. 1H NMR (500 MHz, DMSO-D₆) δ ppm 8.81(s, 1H), 8.05 (s, 1H), 7.79 (d, J=10.07 Hz, 1H), 3.83 (d, J=9.46 Hz,1H), 3.58 (d, J=9.46 Hz, 1H), 2.99 (s, 2H), 2.71-2.80 (m, 2H), 2.61-2.70(m, 2H), 2.00 (s, 1H), 1.83-1.92 (m, 1H), 1.53-1.62 (m, 2H), 1.41-1.50(m, 1H). MS (LC/MS) R.T.=0.52; [M+]′=311.0.

Example 285(R)—N-(6-Chloropyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(6-Chloropyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by the method of Example 267, starting from2-amino-6-chloropyridine. 1H NMR (500 MHz, DMSO-D₆) δ ppm 8.33-8.42 (m,1H), 7.60-7.68 (m, 1H), 6.94 (d, J=7.02 Hz, 1H), 6.72-6.81 (m, 1H), 3.86(d, J=9.46 Hz, 1H), 3.57 (d, J=10.07 Hz, 1H), 2.97 (s, 2H), 2.69-2.78(m, 2H), 2.63-2.68 (m, J=7.63, 7.63 Hz, 2H), 1.95-2.03 (m, 1H),1.83-1.92 (m, 1H), 1.53-1.62 (m, 2H), 1.41-1.49 (m, 1H). MS (LC/MS)R.T.=0.43; [M+H]⁺=293.0.

Example 286(R)—N-(4,6-Dichloropyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(4,6-Dichloropyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by the method of Example 267, starting from2-amino-4,6-dichloropyridine. 1H NMR (500 MHz, DMSO-D6) δ ppm 8.43 (s,1H), 7.13 (s, 1H), 6.84 (s, 1H), 3.86 (d, J=9.77 Hz, 1H), 3.59 (d,J=10.07 Hz, 1H), 2.98 (s, 2H), 2.58-2.86 (m, 4H), 1.94-2.13 (m, 1H),1.78-1.95 (m, 1H), 1.36-1.65 (m, 3H). MS (LC/MS) R.T.=0.87;[M+H]⁺=327.0.

Example 287

(R)—N-(2-Methoxy-3-4′-bipyridin-2′-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: N-(2,4-Dichlorobenzyl)-2,2-diethoxyacetimidamide

To 4-bromopyridin-2-amine (0.5 g, 2.8 mmol),2-methoxypyridin-3-ylboronic acid (0.52 g, 3.4 mmol) in DMF (25 mL) wasadded 1N sodium carbonate (10 mL, 2.3 mmol), followed by1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (0.21 g, 0.26 mmol). The reaction mixture wasstirred for 3 hours at 85° C. and then cooled to room temperature. Theproduct was extracted with ethyl acetate (2×50 mL), dried with MgSO₄,filtered, and concentrated in vacuo. The crude product was purified bychromotography (Biotage: 100 to 90/10% ethyl acetate-ethylacetate/methanol) to yield 2-methoxy-3,4′-bipyridin-2′-amine (0.53 g,2.63 mmol, 93% yield) as a brown powder. The product was taken directlyto the next step.

Step B: 2′-Isothiocyanato-2-methoxy-3,4′-bipyridine

To 2-methoxy-3,4′-bipyridin-2′-amine (0.53 g, 2.63 mmol) indichloromethane (20 mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one(0.62 g, 2.7 mmol) and the reaction mixture was stirred at 40° C. for 4hours. The reaction was cooled to room temperature and chromatographed(Biotage: 10-100% ethyl acetate/hexanes) to yield2′-isothiocyanato-2-methoxy-3,4′-bipyridine (0.46 g, 1.9 mmol, 71.8%yield). 1H NMR (500 MHz, DMSO-D6) δ ppm 8.67 (d, J=2.44 Hz, 1H), 8.26(dd, J=4.88, 1.53 Hz, 1H), 8.15 (dd, J=8.24, 2.44 Hz, 1H), 7.89 (dd,J=7.32, 1.53 Hz, 1H), 7.48 (d, J=8.24 Hz, 1H), 7.15 (dd, J=7.32, 4.88Hz, 1H), 3.91 (s, 3H). MS (LC/MS) R.T.=2.87; [M+H]⁺=244.9.

Step D:(R)—N-(2-Methoxy-3-4′-bipyridin-2′-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To 2′-isothiocyanato-2-methoxy-3,4′-bipyridine (0.09 g, 0.37 mmol) inDMF (20 mL) was added Et₃N (0.11 mL, 0.81 mmol) and(S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.09 g, 0.37 mmol)at room temperature. The reaction was stirred at 70° C. for 2 hours. Thereaction was cooled to room temperature and concentrated in vacuo. Thecrude urea was purified by chromatography (biotage: 85% CHCl₃, 14% MeOH,1% NH₄OH) to yield the pure urea intermediate. The product was thentreated with DMF (20 mL) and N,N′-diisopropylcarbodiimide (0.17 mL, 1.1mmol). The reaction was heated to 90° C. for 18 hours. The reaction wascooled to room temperature and concentrated to yield the crude product.The crude product was purified by chromatography (Biotage: 85% CHCl₃,14% MeOH, 1% NH₄OH) and the product-containing fractions were combined.LC/MS and 1HNMR indicated some impurities may be present. The impureproduct was subjected to reverse phase HPLC to yield(R)—N-(2-methoxy-3,4′-bipyridin-2′-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.02 g, 0.05 mmol, 14.05% yield) as a white powder. 1H NMR (500 MHz,DMSO-D6) δ ppm 9.07 (s, 1H), 8.43 (s, 1H), 8.17 (dd, J=4.73, 1.68 Hz,1H), 7.79 (d, J=7.32 Hz, 2H), 7.10 (dd, J=7.32, 4.88 Hz, 1H), 6.79-6.92(m, 1H), 3.76-3.97 (m, 4H), 3.51-3.66 (m, 1H), 2.92-3.09 (m, 2H),2.59-2.82 (m, 4H), 1.85-2.03 (m, 2H), 1.53-1.71 (m, 2H), 1.35-1.49 (m,1H). MS (LC/MS) R.T.=1.05; [M+H]⁺=366.1.

Example 288(R)—N-(Benzo[d]oxazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: Benzo[d]oxazol-2-amine

An oven dried round bottom flask was charged withdi(1H-imidazol-1-yl)methanimine (500 mg, 3.10 mmol), 2-aminophenol (188mg, 1.724 mmol) and anhydrous THF (20 ml) at room temperature. Theresulting suspension was refluxed under N₂ for 2 hr to give completeconversion based on LC/MS. The solvent was removed in vacuo and theresidue was purified on a Biotage Flash Collector, eluting with 30-80%EtOAc/Hexane (1200 ml) to afford the expected product,benzo[d]oxazol-2-amine (200 mg, 1.5 mmol, 87% yield), as a white solid.1H NMR (400 MHz, CDCl₃) δ ppm 6.20 (br. s., 2H) 7.02-7.11 (m, 1H)7.17-7.22 (m, 1H) 7.29 (d, J=7.53 Hz, 1H) 7.36 (d, J=7.03 Hz, 1H). MS(LC/MS) R.T.=1.05; [M+H]⁺=134.96.

Step B: Dimethyl benzo[d]oxazol-2-ylcarbonimidodithioate

To a colorless solution of benzo[d]oxazol-2-amine (200 mg, 1.491 mmol)in DMF (10 ml) was added sodium hydroxide (20N, 149 μL, 2.98 mmol), togive a green suspension. The mixture was stirred for 15 min at roomtemperature. Carbon disulfide (225 μL, 3.73 mmol) was added to give adark brown solution. The reaction was stirred for 15 min at roomtemperature, followed by the addition of sodium hydroxide (20N, 149 μL,2.98 mmol) and stirred for an additional 10 min. Iodomethane (224 μL,3.58 mmol) was then added dropwise. A green solid precipitated after 12min. The reaction stirred for a further 2 hr. The solid was collected byfiltration, washed with DMF (2×1 ml), H₂O (2×1 ml), dried under thehouse vacuum for 30 min and further dried in an oven in vacuo over nightto afford the expected product, dimethylbenzo[d]oxazol-2-ylcarbonimidodithioate (258.5 mg, 1.085 mmol, 72.7%yield), as a white solid. 1H NMR (400 MHz, CDCl₃) δ ppm 2.70 (s, 6H)7.24-7.34 (m, 2H) 7.45-7.50 (m, 1H) 7.66-7.74 (m, 1H). MS (LC/MS)R.T.=1.76, [M+H]⁺=238.96.

Step C:(R)—N-(Benzo[d]oxazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

A 10 ml-vial was charged with (S)-3-(aminomethyl)quinuclidin-3-ol.2HClsalt (69.5 mg, 0.361 mmol), DMF (2 ml), DIEA (0.063 mL, 0.361 mmol) andCs₂CO₃ (235 mg, 0.722 mmol) at room temperature, followed by dimethylbenzo[d]oxazol-2-ylcarbonimidodithioate (86 mg, 0.361 mmol). Theresulting suspension was stirred at room temperature for 1 hr. LC/MSthen indicated consumption of starting material. The mixture was dilutedwith MeOH and purified by preparative HPLC to afford the expectedproduct,(R)—N-(benzo[d]oxazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(101.5 mg, 0.323 mmol, 90% yield), as a tan gum. 1H NMR (400 MHz,Acetone-d₆) δ ppm 2.07-2.14 (m, 2H) 2.20 (ddd, J=8.78, 5.27, 3.26 Hz,2H) 2.33-2.45 (m, 1H) 2.62 (d, J=2.26 Hz, 1H) 3.34-3.47 (m, 3H)3.48-3.58 (m, 1H) 3.75-3.88 (m, 2H) 4.15 (d, J=10.54 Hz, 1H) 4.32 (d,J=10.54 Hz, 1H) 7.13-7.26 (m, 2H) 7.41 (td, J=3.70, 1.63 Hz, 1H) 9.24(br, s, 1H). MS (LC/MS) R.T.=0.792, [M+H]⁺=299.17.

Example 289(R)—N-(5-Chlorobenzo[d]oxazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: Dimethyl 5-chlorobenzo[d]oxazol-2-ylcarbonimidodithioate

To a brown solution of 5-chlorobenzo[d]oxazol-2-amine (700 mg, 4.15mmol) in DMF (5 ml) was added sodium hydroxide (20N, 415 μL, 8.30 mmol)to give a grey suspension. The mixture was stirred for 15 min at roomtemperature. Carbon disulfide (626 μL, 10.38 mmol) was added at roomtemperature to give a brown solution. The mixture was stirred for 15 minat room temperature, then sodium hydroxide (20N, 208 μL, 4.16 mmol) wasadded. After 10 min, iodomethane (623 μL, 9.97 mmol) was added dropwise.A grey solid came out from solution. The reaction was further stirred atroom temperature for 2 hr. The solid was collected by filtration, washedwith DMF/H₂O (50:50, 2×2 ml), dried under house vacuum for 30 min andfurther dried in an oven at 65° C. under vacuum for 1½ hr to afford theexpected product, dimethyl5-chlorobenzo[d]oxazol-2-ylcarbonimidodithioate (780 mg, 2.86 mmol,68.9% yield), as an off-white solid which was pure enough to be used innext step. 1H NMR (400 MHz, DMSO-d₆) δ ppm 2.69 (s, 6H) 7.37 (dd,J=8.53, 2.26 Hz, 1H) 7.66 (d, J=9.03 Hz, 1H) 7.75 (d, J=1.76 Hz, 1H). MS(LC/MS) R.T.=1.44; [M+H]⁺=272.9.

Step B:(R)—N-(5-Chlorobenzo[d]oxazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

A 10 ml vial was charged with (S)-3-(aminomethyl)quinuclidin-3-ol.2HClsalt (106 mg, 0.550 mmol), DMF (2 ml), DIEA (0.096 mL, 0.550 mmol), andCs₂CO₃ (358 mg, 1.100 mmol) at room temperature, followed by dimethyl5-chlorobenzo[d]oxazol-2-ylcarbonimidodithioate (150 mg, 0.550 mmol).The resulting suspension was stirred at room temperature for 1 hr. LC/MSthen indicated consumption of starting material. The reaction mixturewas diluted with MeOH and purified by preparative HPLC to afford theexpected product,(R)—N-(5-chlorobenzo[d]oxazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(106.5 mg, 0.3 mmol, 53.0% yield), as a white solid. 1H NMR (400 MHz,Acetone-d₆) δ ppm 2.08-2.30 (m, 3H) 2.35-2.48 (m, 1H) 2.60-2.73 (m, 1H)3.48 (qd, J=7.53, 7.28 Hz, 3H) 3.54-3.68 (m, 1H) 3.79-4.00 (m, 2H) 4.18(d, J=10.54 Hz, 1H) 4.35 (d, J=10.54 Hz, 1H) 7.19 (dd, J=8.53, 2.01 Hz,1H) 7.30-7.47 (m, 2H) 9.10 (br. s., 1H). MS(LC/MS) R.T.=1.56;[M+H]⁺=333.13.

Example 290(R)—N-(Oxazolo[4,5-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: Oxazolo[4,5-b]pyridin-2-amine

An oven dried round bottom flask was charged withdi(1H-imidazol-1-yl)methanimine (500 mg, 3.10 mmol), 2-aminopyridin-3-ol(171 mg, 1.551 mmol) and anhydrous THF (20 ml) at room temperature. Theresulting suspension was refluxed under N₂ for 1 hr. LC/MS indicatedcomplete consumption of starting material. The solvent was removed invacuo and the residue was used in the next step without furtherpurification. MS(LC/MS) R.T.=0.235; [M+H]⁺=136.09.

Step B: Dimethyl oxazolo[4,5-b]pyridin-2-ylcarbonimidodithioate

To the crude oxazolo[4,5-b]pyridin-2-amine (811 mg, 6 mmol) from step A,in DMF (12 ml), was added NaOH (20 N, 600 μL, 12.00 mmol) to give a tansolution which was stirred for 15 min at room temperature. Carbondisulfide (904 μL, 15.00 mmol) was then added to give an orangesolution. The mixture was stirred for 15 min at room temperature, thenNaOH (20 N, 600 μL, 12.00 mmol) was added and the stirring continued for10 min to give a dark red solution. Iodomethane (900 μL, 14.40 mmol) wasadded dropwise, resulting in a yellow solid precipitating after 1 hr togive ˜80% conversion. The mixture was diluted with MeOH and purified viapreparative HPLC to afford the expected product, dimethyloxazolo[4,5-b]pyridin-2-ylcarbonimidodithioate (35 mg, 0.146 mmol, 2.4%yield), as a white solid. 1H NMR (400 MHz, CDCl₃) δ ppm 2.71 (s, 6H)7.22 (dd, J=8.03, 5.02 Hz, 1H) 7.72 (dd, J=8.03, 1.25 Hz, 1H) 8.49 (dd,J=5.02, 1.51 Hz, 1H). MS (LC/MS) R.T.=1.358; [M+H]=240.04.

Step C:(R)—N-(Oxazolo[4,5-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

A 10 ml vial was charged with (S)-3-(aminomethyl)quinuclidin-3-ol.2HClsalt (8.53 mg, 0.044 mmol), DMF (2 ml), DIEA (7.74 μL, 0.04 mmol) andCs₂CO₃ (28.9 mg, 0.089 mmol) at room temperature, followed by dimethyloxazolo[4,5-b]pyridin-2-ylcarbonimidodithioate (10.6 mg, 0.044 mmol).The resulting suspension was stirred at room temperature for 1 hr. LC/MSindicated complete consumption of starting material. The reactionmixture was diluted with MeOH and purified via preparative HPLC toafford the expected product,(R)—N-(oxazolo[4,5-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(13 mg, 0.038 mmol, 86% yield), as a white solid. 1H NMR (400 MHz,Acetone-d₆) δ ppm 1.54-1.60 (m, 1H) 1.71-1.77 (m, 2H) 2.16-2.24 (m, 1H)2.77-2.82 (m, 2H) 2.89 (t, J=7.91 Hz, 4H) 3.13-3.25 (m, 2H) 3.90 (d,J=10.29 Hz, 1H) 4.22 (d, J=10.29 Hz, 1H) 7.13 (dd, J=8.03, 5.02 Hz, 1H)7.70 (dd, J=7.91, 1.13 Hz, 1H) 8.27 (dd, J=5.14, 1.13 Hz, 1H) 9.11 (br.s., 1H). MS (LC/MS) R.T.=0.443; [M+H]⁺=300.16.

Example 291(2R)—N-(6,8-Dimethyl-3-isoquinolinyl)-4′H-spiro[4-azabicyclo[2.2.2]octane-2,5′-[1,3]oxazol]-2′-amine

Step A: 6-Methylisoquinolin-3-amine

To a solution of methyl 2,2-diethoxyacetimidate (1.1 g, 6.82 mmol) inmethanol (8 mL) was added p-tolylmethanamine (0.788 g, 6.50 mmol)dropwise at ambient temperature. The reaction flask was then placed intoa preheated oil-bath and stirred at 70° C. for 16 h, then removed andallowed cooled. The volatiles were removed under reduced pressure andthe crude material was added dropwise to sulfuric acid (5 mL) at ambienttemperature. The reaction mixture was stirred for 72 h, then the flaskwas placed into an ice-water bath, diluted with water (50 mL), andslowly neutralized to pH=10 with sodium hydroxide (10 N). As thereaction mixture became basic, a grey precipitate formed. Thisprecipitate was filtered, washed with water, and dried to afford6-methylisoquinolin-3-amine (0.65 g, 63%), as a grey powder. 1H NMR (400MHz, DMSO-d₆) δ ppm 8.73 (s, 1H), 7.69 (d, J=8.28 Hz, 1H), 7.29 (s, 1H),7.00 (d, J=8.28 Hz, 1H), 5.81 (s, 1H), 2.40 (s, 3H). MS (LC/MS)R.T.=1.37; [M+H]⁺=159.10.

Step B: 3-Isothiocyanato-6-methylisoquinoline

To a solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (220 mg, 0.948mmol) in dichloromethane (10 mL) at ambient temperature was added6-methylisoquinolin-3-amine (125 mg, 0.790 mmol). The reaction mixturewas placed into a preheated oil-bath and stirred at 40° C. for 18 h,then removed from the oil-bath and cooled to ambient temperature. Themixture was concentrated and the crude material was purified by silicagel chromatography (5-30% ethyl acetate in hexanes) to afford3-isothiocyanato-6-methylisoquinoline (75 mg, 0.375 mmol, 47.4% yield),as an off-white solid. 1H NMR (400 MHz, CDCl₃) δ ppm 9.03 (s, 1H), 7.88(d, J=8.24 Hz, 1H), 7.56 (s, 1H), 7.46 (dd, J=8.24, 1.53 Hz, 1H), 7.39(s, 1H) 2.57 (s, 3H). MS (LC/MS) R.T.=1.92; [M+H]⁺=201.13.

Step C:(R)—N-(6-Methylisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (65.8 mg, 0.285mmol) in N,N-dimethylformamide (6 mL) was added triethylamine (0.090 mL,0.63 mmol) and 3-isothiocyanato-6-methylisoquinoline (57 mg, 0.285mmol). The suspension was placed into a preheated oil-bath and stirredat 70° C. for 2 h and 30 min. N,N′-diisopropylcarbodiimide (0.177 mL,1.14 mmol) was then added and the mixture was stirred at 85° C. for 16h. The mixture was concentrated and purified by silica gelchromatography (0-40% [9:1 methanol:ammonium hydroxide] in chloroform)followed by purification by reverse phase preparatory HPLC (0-40%TFA-methanol-water). The solution of product was filtered through UCTClean-up CHQAX15M25 cartridge with MeOH (3×10 ml) and concentrated toafford the expected product,(S)-1-((3-hydroxyquinuclidin-3-yl)methyl)-3-(6-methylisoquinolin-3-yl)thiourea,as a tan gum. 1H NMR (400 MHz, MeOD) δ ppm 9.11 (s, 1H), 8.02 (d, J=8.53Hz, 1H), 7.80 (s, 1H), 7.74 (s, 1H), 7.47 (d, J=8.53 Hz, 1H), 4.47 (d,J=10.54 Hz, 1H), 4.31 (d, J=10.54 Hz, 1H), 4.10 (d, J=14.81 Hz, 1H),3.92 (d, J=14.81 Hz, 1H), 3.53-3.71 (m, 2H), 3.27-3.51 (m, 3H), 2.84(br.s, 1H), 2.55 (s, 3H), 2.48 (m, 1H),) 2.10-2.30 (m, 3H). MS (LC/MS)R.T.=1.24; [M+H]⁺=323.2.

Example 292(R)—N-(6-Bromoisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: N-(4-Bromobenzyl)-2,2-diethoxyacetimidamide

(4-Bromophenyl)methanamine hydrochloride (2.359 g, 10.39 mmol) andsodium methoxide (2.376 mL, 10.39 mmol) were added to a solution ofmethyl 2,2-diethoxyacetimidate (3.35 g, 20.78 mmol) in methanol (10 ml).The cloudy mixture was heated at 70 C for 1.5 h and the resulting yellowmixture was concentrated. The residue was purified by silica gel with100% ethyl acetate to give a yellow viscous oil (2.04 g, 62%). ¹H NMR(400 MHz, CDCl₃) δ ppm 7.47 (2H, d, J=8.56 Hz), 7.23 (2H, d, J=8.06 Hz),6.76 (1H, br. s.), 5.31 (1H, br. s.), 4.94 (1H, br. s.), 4.45 (2H, br.s.), 3.47-3.77 (4H, m), 1.26 (6H, t, J=7.05 Hz). LCMS R.T.=2.12;[M+2]⁺=317.2.

Step B: 6-Bromoisoquinolin-3-amine

N-(4-bromobenzyl)-2,2-diethoxyacetimidamide (1.53 g, 4.85 mmol) insulfuric acid (4 mL, 95-98%) was heated at 40 C for 14 h. The mixturewas neutralized with 1 M NaOH to pH 7 and the resulting suspension wasfiltered. The residue was purified by silica gel chromatography with20-55% ethyl acetate in hexanes. The desired fractions were concentratedto give a brownish yellow solid (0.434 g, 40%). LCMS R.T.=1.62;[M+2]⁺=225.1.

Step C: 6-Bromo-3-isothiocyanatoisoquinoline

To a solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (0.251 g, 1.080mmol) in dichloromethane at room temperature was added6-bromoisoquinolin-3-amine (0.241 g, 1.080 mmol). The solution wasstirred at room temperature for 3 hours. LC/MS indicated formation ofthe desired product. The deep orange solution was purified by silica gelchromatography (0-10% ethyl acetate-hexanes) to afford:6-bromo-3-isothiocyanatoisoquinoline (0.1 g, 0.377 mmol, 35% yield) as ayellow oil. R.T.=2.54; [M+H]⁺=267.04.

Step D:(R)—N-(6-bromoisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.086 g, 0.377mmol) in N,N-dimethylformamide (15 mL) was added Cs₂CO₃ (0.307 g, 0.943mmol) and 6-bromo-3-isothiocyanatoisoquinoline (0.1 g, 0.377 mmol). Thesuspension was stirred at room temperature for 30 minutes.N,N′-Diisopropylcarbodiimide (0.176 mL, 1.132 mmol) was then added andthe mixture was stirred for a further 18 hours. The mixture wasconcentrated and purified by silica gel chromatography (5-25% [9.5:0.5methanol:ammonium hydroxide]-ethyl acetate) to afford(R)—N-(6-bromoisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.054 g, 0.135 mmol, 36% yield) as a yellow solid. ¹H NMR (400 MHz,MeOD) δ ppm 9.04 (1H, s), 7.80-8.05 (2H, m), 7.55 (1H, dd, J=8.81, 1.76Hz), 7.37 (1H, br. s.), 4.10 (1H, d, J=10.58 Hz), 3.87 (1H, d, J=10.83Hz), 3.68-3.77 (1H, m), 3.56-3.67 (1H, m), 3.29-3.49 (4H, m), 2.45 (1H,br. s.), 2.28-2.41 (1H, m), 1.86-2.15 (3H, m). LCMS R.T.=1.76;[M+]⁺=387.21.

Example 293(R)—N-(7-Bromoisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: N-(3-Bromobenzyl)-2,2-diethoxyacetimidamide

(3-Bromophenyl)methanamine hydrochloride (3.62 g, 15.64 mmol) and sodiummethoxide (3.58 mL, 15.64 mmol) were added to a solution of methyl2,2-diethoxyacetimidate (5.042 g, 31.3 mmol) in methanol (15 mL). Thecloudy mixture was heated at 70 C for 1.5 h and the resulting yellowmixture was concentrated. The residue was purified by silica gelchromatography with 100% ethyl acetate. The desired fractions wereconcentrated to give a yellow viscous oil (2.5 g, 51%).

LCMS R.T.=2.11; [M+2]⁺=317.06.

Step B: 7-Bromoisoquinolin-3-amine and 5-bromoisoquinolin-3-amine

N-(3-Bromobenzyl)-2,2-diethoxyacetimidamide (2.5 g, 7.93 mmol) insulfuric acid (5 mL, 95-98%) was heated at 40 C for 54 h. The mixturewas neutralized with 10 M NaOH aqueous to pH 7 and the resultingsuspension was filtered. The residue was purified by silica gelchromatography with 20-55% ethyl acetate in hexanes, then 100% ethylacetate. The fractions were concentrated to give a brown solidcontaining a mixture of products. (1.0 g, 57%). LCMS R.T.=1.56;[M+2]⁺=225.1. The mixture was used as is for the next step.

Step C: 7-Bromo-3-isothiocyanatoisoquinoline and5-bromo-3-Isothiocyanatoisoquinoline

To a solution of 1,1′-thiocarbonyldipyridin-2(1H)-one 1.145 g, 4.93mmol) in dichloromethane at room temperature was added the mixture of7-bromoisoquinolin-3-amine and 5-bromoisoquinolin-3-amine from step B(1.0 g, 4.5 mmol). The orange solution was stirred at room temperaturefor 18 hours. LCMS indicated the formation of product. The deep orangesolution was purified by silica gel chromatography (0-5% ethylacetate-hexanes). The first product fractions were combined andconcentrated in vacuo to afford 7-bromo-3-isothiocyanatoisoquinoline(0.27 g, 0.377 mmol, 22% yield) as a yellow solid. ¹H NMR (400 MHz,Acetone) 8 ppm 9.19 (1H, s), 8.41 (1H, s), 7.86-8.02 (2H, m), 7.76 (1H,s). R.T.=4.28; [M+H]⁺=267.04. The second product fractions were combinedand concentrated in vacuo to afford 5-bromo-3-isothiocyanatoisoquinoline(0.25 g, 0.377 mmol, 21% yield) as a yellow solid. ¹H NMR (400 MHz,Acetone) δ ppm 9.24 (1H, s), 8.23 (1H, d), 8.15 (1H, d), 7.81 (1H, s),7.64 (1H, t). LCMS:R.T.=4.61; [M+H]⁺=267.04.

Step D:(R)—N-(7-Bromoisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.207 g, 0.905mmol) in N,N-dimethylformamide (20 mL) was added Cs₂CO₃ (0.737 g, 2.263mmol) and 7-bromo-3-isothiocyanatoisoquinoline (0.24 g, 0.905 mmol). Thesuspension was stirred at room temperature for 30 minutes.N,N′-Diisopropylcarbodiimide (0.423 mL, 2.72 mmol) was then added andthe mixture was stirred at room temperature for 18 hours. The mixturewas concentrated and purified by silica gel chromatography using 5-15%[9:1 methanol:ammonium hydroxide] in ethyl acetate. The desiredfractions were concentrated and further purified using 5-15% [9.5:0.5methanol:ammonium hydroxide] in ethyl acetate to afford((R)—N-(7-bromoisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.061 g, 0.156 mmol, 17% yield) as a yellow solid.

¹H NMR (400 MHz, MeOD) δ ppm 8.96 (1H, s), 8.12 (1H, s), 7.66 (2H, s),7.32 (1H, s), 4.01 (1H, d), 3.73 (1H, d), 3.35-3.42 (1H, m), 3.22-3.29(1H, m), 2.84-3.17 (4H, m), 2.13-2.35 (2H, m), 1.62-1.96 (3H, m).LCMS:R.T.=1.76; [M+]⁺=387.21.

Example 294((R)—N-(5-Bromoisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.207 g, 0.905mmol) in N,N-dimethylformamide (20 mL) was added Cs₂CO₃ (0.737 g, 2.263mmol) and 5-bromo-3-isothiocyanatoisoquinoline (0.24 g, 0.905 mmol). Thesuspension was stirred at room temperature for 30 minutes.N,N′-Diisopropylcarbodiimide (0.423 mL, 2.72 mmol) was then added andthe mixture was stirred at room temperature for 18 hours. The mixturewas concentrated and purified by silica gel chromatography (5-15%[9.5:0.5 methanol:ammonium hydroxide]-ethyl acetate). The desiredfractions were concentrated and further purified using 5-15% [9.5:0.5methanol:ammonium hydroxide] in ethyl acetate to afford(R)—N-(5-bromoisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(0.248 g, 0.634 mmol, 70% yield) as a yellow solid.

¹H NMR (400 MHz, MeOD) δ ppm 8.99 (1H, s), 7.91 (2H, dd), 7.55 (1H, br.s.), 7.28 (1H, t), 3.96 (1H, d), 3.65 (1H, d), 3.17-3.26 (1H, m),3.03-3.13 (1H, m), 2.70-2.99 (4H, m), 2.03-2.30 (2H, m), 1.47-1.87 (3H,m). LCMS R.T.=1.69; [M+2]⁺=389.21.

Example 295(2R)—N-(6,8-Dimethyl-3-isoquinolinyl)-4′H-spiro[4-azabicyclo[2.2.2]octane-2,5′-[1,3]oxazol]-2′-amine

Step A: 6,8-Dimethylisoquinolin-3-amine

To a solution of methyl 2,2-diethoxyacetimidate (1.5 g, 9.3 mmol) inmethanol (4.9 mL) was added (2,4-dimethylphenyl)methanamine (1.2 g, 8.9mmol) dropwise at ambient temperature. The reaction flask was thenplaced into a preheated oil-bath and stirred at 70° C. for 16 h, thencooled and the volatiles removed under reduced pressure. The crudematerial was added dropwise to sulfuric acid (19.7 mL) at ambienttemperature and stirred for 72 h. The flask was then placed into anice-water bath, diluted with water (50 mL), and slowly neutralized topH=10 with sodium hydroxide (10 N). As the reaction mixture becamebasic, an orange precipitate formed. This precipitate was filtered,washed with water, and dried to afford 6,8-dimethylisoquinolin-3-amine(1.37 g, 7.95 mmol, 90%). 1H NMR (400 MHz, MeOD) δ ppm 8.82 (s, 1H),7.17 (s, 1H), 6.90 (s, 1H), 6.72 (s, 1H), 2.61 (s, 3H), 2.37 (s, 3H). MS(LC/MS) R.T.=0.77; [M+H]⁺=173.15.

Step B: 3-Isothiocyanato-6,8-dimethylisoquinoline

To a solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (1.35 g, 5.8 mmol)in dichloromethane (19 mL) at ambient temperature was added6,8-dimethylisoquinolin-3-amine (1 g, 5.8 mmol). The reaction mixturewas placed into a preheated oil-bath and stirred at 40° C. for 18 h,then cooled, concentrated, and the crude material was purified by silicagel chromatography (10-35% ethyl acetate in hexanes) to afford3-isothiocyanato-6,8-dimethylisoquinoline (93.7 mg, 0.437 mmol, 8%) as ayellow solid. 1H NMR (400 MHz, CDCl₃) δ ppm 9.20 (s, 1H), 7.36-7.44 (m,2H), 7.23 (s, 1H), 2.75 (s, 3H), 2.51 (s, 3H). MS (LC/MS) R.T.=2.03;[M+H]⁺=215.1.

Step C:(2R)—N-(6,8-Dimethyl-3-isoquinolinyl)-4′H-spiro[4-azabicyclo[2.2.2]octane-2,5′-[1,3]oxazol]-2′-amine

To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (99 mg, 0.43mmol) in N,N-dimethylformamide (1.4 mL) was added triethylamine (0.18mL, 1.3 mmol) and 3-isothiocyanato-6,8-dimethylisoquinoline (93 mg, 0.43mmol). The suspension was placed into a preheated oil-bath and stirredat 70° C. for 2 h and 30 min. N,N′-Diisopropylcarbodiimide (0.27 mL, 1.7mmol) was then added and the mixture was stirred at 85° C. for 16 h. Themixture was concentrated and purified by silica gel chromatography(0-40% [9:1 methanol:ammonium hydroxide] in chloroform) followed bypurification by reverse phase preparative HPLC (0-40% [0.1%TFA]-methanol-water) to afford(2R)—N-(6,8-dimethyl-3-isoquinolinyl)-4′H-spiro[4-azabicyclo[2.2.2]octane-2,5′-[1,3]oxazol]-2′-amineas the trifluoroacetic acid salt (24 mg, 0.053 mmol, 12% yield) as awhite solid. 1H NMR (400 MHz, MeOD) δ ppm 9.29 (s, 1H), 7.54 (s, 1H),7.43 (s, 1H), 7.34 (s, 1H), 4.38 (d, J=11.04 Hz, 1H), 4.17 (d, J=11.04Hz, 1H), 3.94-4.10 (m, 1H), 3.86 (dd, J=15.06, 2.26 Hz, 1H), 3.51-3.67(m, 1H), 3.37-3.51 (m, 3H), 2.77 (s, 3H), 2.73 (d, J=3.51 Hz, 1H),2.48-2.57 (m, 3H), 2.30-2.46 (m, 1H), 1.94-2.28 (m, 3H). MS (LC/MS)R.T.=0.90; [M+H]⁺=337.38.

Example 296(R)—N-(3,4′-Bipyridin-2′-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(3,4′-Bipyridin-2′-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared from 4-bromopyridin-2-amine, pyridin-3-ylboronic acid, and1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex by following the general procedures of Example28, Steps A-B. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.95 (br. s., 2H), 8.66(d, J=4.6 Hz, 1H), 8.31 (d, J=5.5 Hz, 1H), 8.14 (br. s., 1H), 7.54 (d,J=7.6 Hz, 1H), 7.26 (br. s., 2H), 3.85 (br. s., 1H), 3.58 (s, 1H), 3.00(br. s., 2H), 2.67 (br. s., 4H), 1.90 (br. s., 2H), 1.59 (br. s., 2H),1.45 (br. s., 1H). MS (LC/MS) R.T.=0.12; [M+H]⁺=336.18.

Example 297(R)—N-(5-Chloro-3,4′-bipyridin-2′-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(5-Chloro-3,4′-bipyridin-2′-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared from 4-bromopyridin-2-amine, 5-chloropyridin-3-ylboronicacid, and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex by following the general procedures of Example28, Steps A-B. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.92 (s, 2H), 8.71 (d,J=2.1 Hz, 1H), 8.19-8.39 (m, 2H), 7.30 (d, J=4.3 Hz, 2H), 3.77-3.95 (m,1H), 3.59 (d, J=10.1 Hz, 1H), 3.01 (d, J=4.9 Hz, 2H), 2.61-2.86 (m, 4H),2.00 (s, 1H), 1.83-1.96 (m, 1H), 1.55-1.68 (m, 2H), 1.40-1.54 (m, 1H).MS (LC/MS) R.T.=0.91; [M+H]⁺=370.09.

Example 298

(R)—N-(6-Methoxy-3,4′-bipyridin-2′-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(6-Methoxy-3,4′-bipyridin-2′-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared from 4-bromopyridin-2-amine, 6-methoxypyridin-3-ylboronicacid, and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex by following the general procedures of Example28, Steps A-B. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.79-9.21 (m, 1H),8.46-8.66 (m, 1H), 8.26 (s, 1H), 7.97-8.14 (m, 1H), 6.99-7.27 (m, 2H),6.83-6.99 (m, 1H), 3.92 (s, 4H), 3.49-3.62 (m, 1H), 2.99 (d, J=4.3 Hz,2H), 2.66 (d, J=7.6 Hz, 4H), 1.79-2.05 (m, 2H), 1.33-1.63 (m, 3H). MS(LC/MS) R.T.=0.98; [M+H]⁺=366.17.

Example 299(R)—N-(6-Fluoro-3,4′-bipyridin-2′-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(6-Fluoro-3,4′-bipyridin-2′-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared from 4-bromopyridin-2-amine,2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, and1,1′-bis(diphenylphosphino) ferrocene-palladium(II)dichloridedichloromethane complex by following the general procedures of Example28, Steps A-B. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.90-9.17 (m, 1H),8.57-8.71 (m, 1H), 8.31 (d, J=5.5 Hz, 2H), 7.31-7.40 (m, 1H), 7.01-7.29(m, 2H), 3.76-3.95 (m, 1H), 3.59 (d, J=10.4 Hz, 1H), 3.01 (br. s., 2H),2.68 (br. s., 4H), 1.95-2.05 (m, 1H), 1.81-1.95 (m, 1H), 1.59 (br. s.,2H), 1.37-1.53 (m, 1H). MS (LC/MS) R.T.=0.68; [M+H]⁺=354.09.

Example 300 (R)—N-(4-(3-Chloro-4fluoro-phenyl)pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(4-(3-Chloro-4-fluoro-phenyl)pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared from 4-bromopyridin-2-amine, 3-chloro-4-fluorophenylboronicacid, and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloridedichloromethane complex by following the general procedures of Example28, Steps A-B. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.92-9.16 (m, 1H), 8.28(d, J=5.2 Hz, 1H), 7.88-8.09 (m, 1H), 7.66-7.81 (m, 1H), 7.43-7.63 (m,1H), 7.19-7.30 (m, 1H), 6.99-7.17 (m, 1H), 3.77-3.94 (m, 1H), 3.53-3.66(m, 1H), 2.99 (br. s., 2H), 2.67 (br. s., 4H), 1.82-2.03 (m, 2H),1.52-1.66 (m, 2H), 1.37-1.53 (m, 1H). MS (LC/MS) R.T.=1.65;[M+H]⁺=387.10.

Example 301(R)—N-(4-m-Tolylpyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(4-m-Tolylpyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared from 4-bromopyridin-2-amine, m-tolylboronic acid, and1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex by following the general procedures of Example28, Steps A-B. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.86-9.25 (m, 1H), 8.26(d, J=5.5 Hz, 1H), 7.45-7.57 (m, 2H), 7.39 (t, J=7.5 Hz, 1H), 7.27 (d,J=7.3 Hz, 1H), 7.18 (d, J=4.3 Hz, 2H), 3.76-3.98 (m, 1H), 3.58 (d,J=10.4 Hz, 1H), 2.99 (d, J=5.8 Hz, 2H), 2.72-2.85 (m, 2H), 2.67 (t,J=7.6 Hz, 2H), 2.39 (s, 3H), 1.83-2.05 (m, 2H), 1.52-1.64 (m, 2H),1.36-1.51 (m, 1H). MS (LC/MS) R.T.=1.54; [M+H]⁺=349.19.

Example 302(R)—N-(4-Phenylpyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(4-Phenylpyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared from 4-bromopyridin-2-amine by following the generalprocedures of Example 28, Steps A-B. ¹H NMR (500 MHz, DMSO-d₆) δ ppm8.91-9.29 (m, 1H), 8.27 (d, J=5.5 Hz, 1H), 7.73 (d, J=7.3 Hz, 2H),7.38-7.58 (m, 3H), 6.92-7.27 (m, 2H), 3.78-3.94 (m, 1H), 3.59 (d, J=10.4Hz, 1H), 2.91-3.08 (m, 2H), 2.59-2.87 (m, 4H), 1.82-2.05 (m, 2H), 1.59(br. s., 2H), 1.36-1.53 (m, 1H). MS (LC/MS) R.T.=1.24; [M+H]⁺=335.15.

Example 303(R)—N-(4-(1-Methyl-1H-pyrazol-4-yl)pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(4-(1-Methyl-1H-pyrazol-4-yl)pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared from 4-bromopyridin-2-amine,1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,and 1,1′-bis(diphenyl phosphino)ferrocene-palladium(II)dichloridedichloromethane complex by following the general procedures of Example28, Steps A-B. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.80-9.17 (m, 1H), 8.26(s, 1H), 8.14 (d, J=5.2 Hz, 1H), 7.94 (br. s., 1H), 7.06 (d, J=4.3 Hz,2H), 3.88 (s, 4H), 3.56 (d, J=9.8 Hz, 1H), 2.98 (br. s., 2H), 2.60-2.86(m, 4H), 1.79-2.07 (m, 2H), 1.58 (br. s., 2H), 1.46 (dd, J=9.6, 2.6 Hz,1H). MS (LC/MS) R.T.=0.7; [M+H]⁺=339.18.

Example 304(R)—N-(4-Tthiazol-4-yl)pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(4-(Thiazol-4-yl)pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared from 4-bromopyridin-2-amine, 4-(tributylstannyl)thiazole,and 1,1′-bis(diphenyl phosphino)ferrocene-palladium(II) dichloridedichloromethane complex by following the general procedures of Example28, Steps A-B. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.25 (d, J=1.8 Hz, 2H),8.40 (s, 1H), 8.27 (d, J=5.5 Hz, 1H), 7.23-7.53 (m, 2H), 3.85 (br. s.,1H), 3.58 (d, J=10.4 Hz, 1H), 3.00 (d, J=6.7 Hz, 2H), 2.73-2.85 (m, 2H),2.68 (t, J=7.8 Hz, 2H), 1.84-2.04 (m, 2H), 1.53-1.68 (m, 2H), 1.47 (d,J=7.0 Hz, 1H). MS (LC/MS) R.T.=0.78; [M+H]⁺=342.17.

Example 305(R)—N-(6-Nitro-3,4′-bipyridin-2′-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(6-Nitro-3,4′-bipyridin-2′-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared from 4-bromopyridin-2-amine,2-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, and1,1′-bis(diphenylphosphino) ferrocene-palladium(II) dichloridedichloromethane complex by following the general procedures of Example28, Steps A-B. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.06 (br. s., 2H),8.52-8.67 (m, 1H), 8.31-8.46 (m, 2H), 7.13-7.44 (m, 2H), 3.78-3.94 (m,1H), 3.60 (d, J=10.1 Hz, 1H), 3.00 (br. s., 2H), 2.59-2.84 (m, 4H), 2.00(br. s., 2H), 1.59 (br. s., 2H), 1.38-1.53 (m, 1H). MS (LC/MS)R.T.=0.81; [M+H]⁺=381.2.

Example 306(R)—N-(5-Chloro-6-methylpyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(5-Chloro-6-methylpyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by following the general procedures of Example 23, StepsA-B using 5-chloro-6-methylpyridin-2-amine as the starting material. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 8.81 (br. s., 1H), 7.59 (br. s., 1H), 6.64(br. s., 1H), 3.82 (br. s., 1H), 3.56 (d, J=10.4 Hz, 1H), 2.97 (s, 2H),2.58-2.82 (m, 4H), 2.48 (br. s., 3H), 1.98 (br. s., 1H), 1.81-1.93 (m,1H), 1.58 (br. s., 2H), 1.28-1.51 (m, 1H). MS (LC/MS) R.T.=0.89;[M+H]⁺=307.08.

Example 307(R)—N-(5-Fluoro-4-methylpyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(5-Fluoro-4-methylpyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by following the general procedures of Example 23, StepsA-B using 5-fluoro-4-methylpyridin-2-amine as the starting material. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 8.59-8.97 (m, 1H), 8.04 (s, 1H), 6.50-6.95(m, 1H), 3.79 (br. s., 1H), 3.53 (d, J=10.4 Hz, 1H), 2.96 (br. s., 2H),2.60-2.84 (m, 4H), 2.21 (s, 3H), 1.95 (br. s., 2H), 1.52-1.66 (m, 2H),1.45 (ddd, J=6.9, 2.9, 2.7 Hz, 1H). MS (LC/MS) R.T.=0.63; [M+H]⁺=291.12.

Example 308(R)—N-(3,5-Dichloro-6-methylpyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(3,5-Dichloro-6-methylpyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by following the general procedures of Example 23, StepsA-B using 3,5-dichloro-6-methylpyridin-2-amine as the starting material.¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.83 (br. s., 1H), 7.86 (d, J=2.1 Hz,1H), 3.85 (d, J=9.8 Hz, 1H), 3.59 (d, J=10.1 Hz, 1H), 3.00 (br. s., 1H),2.73-2.84 (m, 1H), 2.67 (t, J=7.5 Hz, 1H), 2.49 (dd, J=14.5, 2.0 Hz,6H), 2.01 (br. s., 1H), 1.89 (br. s., 1H), 1.59 (br. s., 2H), 1.37-1.51(m, 1H). MS (LC/MS) R.T.=1.07; [M+H]⁺=341.06.

Example 309(R)—N-(4,5-Dimethylpyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(4,5-Dimethylpyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by following the general procedures of Example 23, StepsA-B using 4,5-dimethylpyridin-2-amine as the starting material.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.71-9.29 (m, 1H), 7.92 (s, 1H),6.28-7.02 (m, 1H), 3.80 (br. s., 1H), 3.53 (d, J=10.1 Hz, 1H), 2.87-3.03(m, 2H), 2.59-2.85 (m, 4H), 2.04-2.26 (m, 6H), 1.80-1.99 (m, 2H),1.33-1.64 (m, 3H). MS (LC/MS) R.T.=0.67; [M+H]⁺=287.20.

Example 310(R)—N-(5-Methoxypyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(5-Methoxypyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by following the general procedures of Example 23, StepsA-B using 5-methoxypyridin-2-amine as the starting material.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.57-9.10 (m, 1H), 7.91 (d, J=3.1 Hz,1H), 7.30 (dd, J=8.9, 3.4 Hz, 1H), 6.54-7.04 (m, 1H), 3.72-3.85 (m, 4H),3.52 (d, J=10.1 Hz, 1H), 2.88-3.03 (m, 2H), 2.76 (d, J=5.8 Hz, 2H), 2.66(t, J=7.6 Hz, 2H), 1.81-2.02 (m, 2H), 1.51-1.64 (m, 2H), 1.38-1.49 (m,1H). MS (LC/MS) R.T.=0.46; [M+H]⁺=289.17.

Example 311(R)—N-(4-Chloroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 4-Chloroisoquinolin-3-amine

To isoquinolin-3-amine (2.02 g, 14.0 mmol) in methanol (60 mL) was addedN-chlorosuccinimide (2.19 g, 16.4 mmol) at room temperature. Thereaction was stirred at room temperature for 3 hours, then concentratedin vacuo. The crude material was chromatographed (Biotage: 10-100% ethylacetate/hexanes) to yield 4-chloroisoquinolin-3-amine (2.1 g, 11.8 mmol,84% yield) as a solid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.86 (s, 1H),7.93 (d, J=7.6 Hz, 1H), 7.79 (d, J=8.5 Hz, 1H), 7.68 (td, J=6.7, 1.8 Hz,1H), 7.24-7.35 (m, 1H), 6.32 (br. s., 2H). MS (LC/MS) R.T.=1.50;[M+H]⁺=178.96.

Step B:(R)—N-(4-Chloroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(4-Chloroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by following the general procedures of Example 267, StepsA-B using 4-chloroisoquinolin-3-amine (from Step A above) as thestarting material. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.98-9.10 (m, 1H),8.57-8.95 (m, 1H), 7.99-8.18 (m, 2H), 7.79 (s, 1H), 7.51 (s, 1H), 3.84(d, J=9.8 Hz, 1H), 3.35-3.51 (m, 1H), 3.02 (d, J=5.5 Hz, 2H), 2.78 (s,2H), 2.61-2.73 (m, 2H), 2.00 (s, 2H), 1.55-1.65 (m, 2H), 1.42-1.54 (m,1H). MS (LC/MS) R.T.=0.92; [M+H]⁺=343.09.

Example 312(R)—N-(7-Chloro-8-fluoroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: N-(3-Chloro-2-fluorobenzyl)-2,2-diethoxyacetimidamide

(3-Chloro-2-fluorophenyl)methanamine (1.0 g, 6.27 mmol) was added to asolution of methyl 2,2-diethoxyacetimidate (1.12 g, 6.96 mmol) inmethanol (10 ml). The mixture was heated at 70 C for 1 h. The mixturewas purified by chromatography (Biotage: 100% ethyl acetate) to yieldN-(3-chloro-2-fluorobenzyl)-2,2-diethoxyacetimidamide (1.3 g, 4.5 mmol,65% yield) as a colorless viscous oil.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.23-7.40 (m, 2H), 7.07 (t, J=7.9Hz, 1H), 4.93 (s, 1H), 4.54 (s, 2H), 3.50-3.74 (m, 4H), 1.18-1.35 (m,6H). MS (LC/MS) R.T.=1.78; [M+H]⁺=289.17.

Step B: 7-Chloro-8-fluoroisoquinolin-3-amine

To N-(3-chloro-2-fluorobenzyl)-2,2-diethoxyacetimidamide (0.97 g, 3.36mmol) was added sulfuric acid (4 mL, 75 mmol). The reaction was heatedto 40° C. for 28 hours. The reaction was cooled to room temperature andquenched with aq. sodium hydroxide (˜15 M) until the reaction mixturewas ˜pH 7. The crude product was extracted with ethyl acetate (2×50 mL)and the organics were dried with MgSO₄, filtered, and concentrated invacuo. The crude product was purified by chromatography (Biotage: 100%ethyl acetate to 90/10% ethyl acetate/MeOH) to yield7-chloro-8-fluoroisoquinolin-3-amine (0.58 g, 2.95 mmol, 88% yield) as apowder. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.97 (s, 1H), 7.47-7.57 (m, 1H),7.38-7.45 (m, 1H), 6.67 (s, 1H), 6.33 (s, 2H). MS (LC/MS) R.T.=1.18;[M+H]⁺=196.95.

Step C:(R)—N-(7-Chloro-8-fluoroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(7-Chloro-8-fluoroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by following the general procedures of Example 267, StepsA-B using 7-chloro-8-fluoroisoquinolin-3-amine (from Step B above) asthe starting material. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.19 (d, J=2.1Hz, 1H), 8.30-8.85 (m, 1H), 7.68 (br. s., 2H), 6.93-7.43 (m, 1H),3.73-4.10 (m, 1H), 3.48-3.70 (m, 1H), 3.02 (br. s., 2H), 2.59-2.86 (m,4H), 1.80-2.08 (m, 2H), 1.60 (br. s., 2H), 1.37-1.53 (m, 1H). MS (LC/MS)R.T.=1.22; [M+H]⁺=361.06.

Example 313(R)—N-(1-Methylisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(1-Methylisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by following the general procedures of Example 312, StepsA-C using 1-phenylethanamine as the starting material. ¹H NMR (500 MHz,MeOD) δ ppm 8.10 (d, J=8.2 Hz, 1H), 7.72 (d, J=8.2 Hz, 1H), 7.60 (t,J=7.5 Hz, 1H), 7.44 (t, J=7.6 Hz, 1H), 7.03-7.33 (m, 1H), 4.01 (d,J=10.1 Hz, 1H), 3.69 (d, J=10.1 Hz, 1H), 3.19-3.31 (m, 2H), 3.12 (d,J=15.0 Hz, 1H), 2.90-3.01 (m, 5H), 2.77-2.90 (m, 2H), 2.17 (br. s., 2H),1.58-1.87 (m, 3H). MS (LC/MS) R.T.=1.09; [M+H]⁺=323.16.

Example 314(R)—N-(6-(4-Fluorophenyl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(6-(4-Fluorophenyl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by the method of Example 256, steps A-C, starting from6-chloropyrimidin-4-amine and 4-fluorophenylboronic acid. ¹H NMR (400MHz, MeOD) δ ppm 8.75 (1H, s), 7.93-8.11 (2H, m), 7.06-7.30 (3H, m),4.03 (1H, d, J=10.32 Hz), 3.73 (1H, d, J=10.32 Hz), 3.18-3.27 (1H, m),3.05-3.16 (1H, m), 2.66-3.00 (4H, m), 2.01-2.20 (2H, m), 1.49-1.87 (3H,m). LC/MS RT=1.53; [M+H]⁺=354.24.

Example 315(R)—N-(6-(3-Fluorophenyl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(6-(3-Fluorophenyl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by the method of Example 256, steps A-C, starting from6-chloropyrimidin-4-amine and 3-fluorophenylboronic acid. ¹H NMR (400MHz, MeOD) δ ppm 8.80 (1H, d, J=1.26 Hz), 7.71-7.85 (2H, m), 7.50 (1H,td, J=7.99, 5.92 Hz), 7.11-7.36 (2H, m), 4.08 (1H, d, J=10.58 Hz), 3.80(1H, d, J=10.58 Hz), 3.39-3.48 (1H, m), 3.33 (1H, s), 2.83-3.20 (4H, m),2.10-2.33 (2H, m), 1.65-1.96 (3H, m). LC/MS RT=1.59; [M+H]⁺=354.24.

Example 316(R)—N-(5-Fluoropyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(5-Fluoropyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by the method of Example 231, steps B-C, starting from2-chloro-5-fluoropyrimidine. ¹H NMR (400 MHz, MeOD) δ ppm 8.50 (2H, d,J=0.76 Hz), 4.03 (1H, d, J=10.07 Hz), 3.77 (1H, d, J=10.32 Hz),3.47-3.57 (1H, m), 3.36-3.43 (1H, m), 3.01-3.24 (4H, m), 2.15-2.40 (2H,m), 1.68-2.03 (3H, m). LC/MS RT=0.30; [M+H]⁺=278.19.

Example 317(R)—N-(4-Chloro-5-methoxypyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(4-Chloro-5-methoxypyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by the method of Example 231, steps B-C, starting from2,4-dichloro-5-methoxypyrimidine. ¹H NMR (400 MHz, MeOD) δ ppm 7.99 (1H,s), 4.13 (1H, d, J=10.83 Hz), 3.91 (4H, d, J=10.83 Hz), 3.76-3.84 (1H,m), 3.64-3.71 (1H, m), 3.30-3.51 (4H, m), 2.43-2.52 (1H, m), 2.37 (1H,d, J=3.27 Hz), 2.09 (1H, dd, J=9.32, 4.78 Hz), 1.88-2.03 (2H, m). LC/MSRT=0.30; [M+H]⁺=278.19.

Example 318(R)—N-(6,8-Difluoroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(6,8-Difluoroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by the method of Example 279, steps A-D, starting from(3,5-difluorophenyl)methanamine. MS (LC/MS) R.T.=1.42; [M+H]⁺=345.26.

Example 319(R)—N-(6,7-Difluoroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(6,7-Difluoroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by the method of Example 279, steps A-D, starting from(3,4-difluorophenyl)methanamine. ¹H NMR (500 MHz, MeOD) δ ppm 8.97 (1H,s), 7.73-7.91 (1H, m), 7.58 (1H, dd, J=11.14, 7.78 Hz), 7.30 (1H, s),4.01 (1H, d, J=10.07 Hz), 3.71 (1H, d, J=10.07 Hz), 3.31 (1H, br. s.),3.14-3.24 (1H, m), 3.03 (2H, d, J=7.32 Hz), 2.83-2.98 (2H, m), 2.20 (2H,br. s.), 1.61-1.91 (3H, m). MS (LC/MS) R.T.=1.45; [M+H]⁺=345.26.

Example 320(R)—N-(5,8-Difluoroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(

(R)—N-(5,8-Difluoroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by the method of Example 279, steps A-D, starting from(2,5-difluorophenyl)methanamine. ¹H NMR (500 MHz, MeOD) δ ppm 9.25 (1H,s), 7.43 (1H, br. s.), 7.20-7.34 (1H, m), 6.91-7.12 (1H, m), 4.04 (1H,d, J=10.07 Hz), 3.74 (1H, d, J=10.07 Hz), 3.30 (1H, br. s.), 3.13-3.23(1H, m), 3.03 (2H, d, J=7.63 Hz), 2.82-2.96 (2H, m), 2.21 (2H, br. s.),1.58-1.92 (3H, m). MS (LC/MS) R.T.=1.37; [M+H]⁺=345.33.

Example 321(R)—N-(7-Fluoroquinazolin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(7-Fluoroquinazolin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by the method of Example 239, steps A-B, starting from7-fluoroquinazolin-2-amine ¹H NMR (400 MHz, MeOD) δ ppm 9.22 (1H, s),7.95 (1H, dd, J=8.81, 6.04 Hz), 7.47 (1H, dd, J=10.45, 2.14 Hz), 7.24(1H, td, J=8.75, 2.39 Hz), 4.07 (1H, d, J=10.07 Hz), 3.77 (1H, d,J=10.07 Hz), 3.25 (1H, s), 3.07-3.17 (1H, m), 2.89-3.02 (2H, m),2.75-2.88 (2H, m), 2.04-2.26 (2H, m), 1.50-1.85 (3H, m). MS (LC/MS)R.T.=1.06; [M+H]⁺=328.33.

Example 322(R)—N-(5-Chloroquinazolin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(5-Chloroquinazolin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by the method of Example 239, steps A-B, starting from5-chloroquinazolin-2-amine ¹H NMR (400 MHz, MeOD) δ ppm 9.53 (1H, s),7.62-7.84 (2H, m), 7.47 (1H, dd, J=6.80, 1.51 Hz), 4.09 (1H, d, J=10.32Hz), 3.80 (1H, d, J=10.32 Hz), 3.36 (1H, s), 3.15-3.24 (1H, m), 3.00(2H, t, J=7.68 Hz), 2.79-2.95 (2H, m), 2.05-2.32 (2H, m), 1.53-1.87 (3H,m). MS (LC/MS) R.T.=1.36; [M+H]⁺=344.29

Example 323(R)—N-(5-Fluoroquinazolin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(5-Fluoroquinazolin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by the method of Example 239, steps A-B, starting from5-fluoroquinazolin-2-amine. ¹H NMR (400 MHz, MeOD) δ ppm 9.46 (1H, s),7.77 (1H, td, J=8.18, 6.30 Hz), 7.63 (1H, d, J=8.56 Hz), 7.00-7.20 (1H,m), 4.08 (1H, d, J=10.07 Hz), 3.77 (1H, d, J=10.07 Hz), 3.25 (1H, s),3.07-3.17 (1H, m), 2.94 (2H, t, J=7.68 Hz), 2.72-2.88 (2H, m), 2.05-2.21(2H, m), 1.48-1.83 (3H, m). MS (LC/MS) R.T.=1.10; [M+H]⁺=328.33

Example 324(R)—N-(7-Fluoro-4-methylquinazolin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(7-Fluoro-4-methylquinazolin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by the method of Example 239, steps A-B, starting from7-fluoro-4-methylquinazolin-2-amine. ¹H NMR (400 MHz, MeOD) δ ppm 8.13(1H, dd, J=9.07, 6.04 Hz), 7.46 (1H, dd, J=10.45, 2.64 Hz), 7.22 (1H,td, J=8.81, 2.77 Hz), 4.06 (1H, d, J=10.07 Hz), 3.75 (1H, d, J=10.07Hz), 3.23 (1H, s), 3.06-3.15 (1H, m), 2.94 (2H, t, J=7.68 Hz), 2.73-2.88(5H, m), 2.06-2.24 (2H, m), 1.51-1.86 (3H, m). MS (LC/MS) R.T.=1.25;[M+H]⁺=342.29.

Example 325(R)—N-(6-Fluoro-1-methylisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(6-Fluoro-1-methylisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by the method of Example 279, steps A-D, starting from(S)-1-(4-fluorophenyl)ethanamine. ¹H NMR (500 MHz, MeOD) δ ppm 8.23 (1H,dd, J=9.16, 5.49 Hz), 7.44 (1H, dd, J=9.92, 2.59 Hz), 7.22-7.38 (2H, m),4.17 (1H, d, J=10.99 Hz), 3.94 (1H, d, J=10.68 Hz), 3.71-3.79 (1H, m),3.61-3.69 (1H, m), 3.39-3.49 (1H, m), 3.33-3.39 (3H, m), 2.95 (3H, s),2.49 (1H, br. s.), 2.37 (1H, tt, J=10.07, 3.36 Hz), 2.05-2.16 (1H, m),1.93-2.05 (2H, m).

MS (LC/MS) R.T.=1.47; [M+H]⁺=341.25.

Example 326(R)—N-(6-Chloro-1-methylisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(6-Chloro-1-methylisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by the method of Example 279, steps A-D, starting from1-(4-chlorophenyl)ethanamine, ¹H NMR (500 MHz, MeOD) δ ppm 8.23 (1H, dd,J=9.16, 5.49 Hz), 7.44 (1H, dd, J=9.92, 2.59 Hz), 7.22-7.38 (2H, m),4.17 (1H, d, J=10.99 Hz), 3.94 (1H, d, J=10.68 Hz), 3.71-3.79 (1H, m),3.61-3.69 (1H, m), 3.39-3.49 (1H, m), 3.33-3.39 (3H, m), 2.95 (3H, s),2.49 (1H, br. s.), 2.37 (1H, tt, J=10.07, 3.36 Hz), 2.05-2.16 (1H, m),1.93-2.05 (2H, m). MS (LC/MS) R.T.=1.79; [M+H]⁺=357.28

Example 327(R)—N-(7-Fluoro-1-methylisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(7-Fluoro-1-methylisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by the method of Example 279, steps A-D, starting from1-(3-fluorophenyl)ethanamine. ¹H NMR (400 MHz, MeOD) δ ppm 7.55-7.81(2H, m), 7.38 (1H, t, J=7.55 Hz), 7.16 (1H, br. s.), 3.95 (1H, d, J=9.82Hz), 3.64 (1H, d, J=9.82 Hz), 3.20 (1H, d, J=14.86 Hz), 3.01-3.13 (1H,m), 2.63-2.97 (7H, m), 2.11 (2H, br. s.), 1.41-1.81 (3H, m). MS (LC/MS)R.T.=1.63; [M+H]⁺=341.32.

Example 328(R)—N-(5,7-Difluoro-1-methylisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(5,7-Difluoro-1-methylisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by the method of Example 279, steps A-D, starting from1-(3,5-difluorophenyl)ethanamine. ¹H NMR (500 MHz, MeOD) δ ppm 7.78 (1H,d, J=9.77 Hz), 7.39-7.55 (2H, m), 4.31 (1H, d, J=10.99 Hz), 4.11 (1H, d,J=10.99 Hz), 3.88-3.97 (1H, m), 3.79-3.86 (1H, m), 3.55 (1H, t, J=11.90Hz), 3.37-3.47 (3H, m), 3.00 (3H, s), 2.64 (1H, br. s.), 2.32-2.45 (1H,m), 2.18 (1H, dddd, J=11.71, 7.13, 6.94, 6.56 Hz), 1.99-2.13 (2H, m). MS(LC/MS) R.T.=1.67; [M+H]⁺=359.22.

Example 329(R)—N-(6-(6-(Methylthio)pyridin-3-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(6-(6-(Methylthio)pyridin-3-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by the method of Example 261, steps A-B, starting from6-(6-fluoropyridin-3-yl)pyrimidin-4-amine. ¹H NMR (400 MHz, MeOD) δ ppm9.02 (1H, d, J=2.52 Hz), 8.78 (1H, s), 8.20 (1H, dd, J=8.44, 2.39 Hz),7.36 (1H, d, J=8.56 Hz), 7.26 (1H, br. s.), 4.06 (1H, d, J=10.58 Hz),3.77 (1H, d, J=10.32 Hz), 3.34 (1H, s), 3.14-3.22 (1H, m), 2.82-3.08(4H, m), 2.58 (3H, s), 2.08-2.24 (2H, m), 1.60-1.88 (3H, m). MS (LC/MS)R.T.=3.09; [M+H]⁺=383.2.

Example A 330(R)—N-(6-(2-Fluoropyridin-3-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 6-(2-Fluoropyridin-3-yl)pyrimidin-4-amine

A mixture of 6-chloropyrimidin-4-amine (1.5 g, 11.58 mmol),2-fluoropyridin-3-ylboronic acid (2.039 g, 14.47 mmol), and Na₂CO₃ (3.68g, 34.7 mmol) was suspended in a mixture of dioxane (15 mL)/EtOH (2mL)/water (3 mL). The mixture was heated in the microwave synthesizer at125° C. for 20 min, concentrated, and purified on a silica gel cartridgeusing 10-60% ethyl acetate in hexanes, then 5-25% 9: methanol:ammoniumhydroxide in ethyl acetate to give an off-white solid (1.5 g, 7.89 mmol,68%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.57 (1H, ddd, J=9.95, 7.68, 2.01Hz), 8.48 (1H, d, J=1.26 Hz), 8.33 (1H, td, J=3.02, 2.01 Hz), 7.51 (1H,ddd, J=7.37, 4.97, 2.01 Hz), 7.12 (2H, br. s.), 6.96 (1H, d, J=1.26 Hz).MS (LC/MS) R.T.=0.43; [M+H]⁺=191.15.

Step B: 4-(2-Fluoropyridin-3-yl)-6-isothiocyanatopyrimidine

To a solution of 6-(2-fluoropyridin-3-yl)pyrimidin-4-amine (0.3 g, 1.577mmol) in DMF was added NaH (0.126 g, 3.15 mmol). Stirring was continuedfor 1.5 h and 1,1′-thiocarbonyldipyridin-2(1H)-one (0.366 g, 1.577 mmol)was added. The mixture was stirred at rt for 2 h and purified on silicagel using 10-15% ethyl acetate in hexanes to give an orange solid (0.133g, 0.573 mmol, 36%). MS (LC/MS) R.T.=2.48; [M+H]⁺=233.08.

Step C:(S)-1-(6-(2-Fluoropyridin-3-yl)pyrimidin-4-yl)-3-((3-hydroxyquinuclidin-3-yl)methyl)thiourea

To (4-(2-fluoropyridin-3-yl)-6-isothiocyanatopyrimidine (0.18 g, 0.775mmol) in N,N-dimethylformamide (20 mL) was added Cs₂CO₃ (0.631 g, 1.938mmol) and (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.178 g,0.775 mmol). The suspension was stirred at room temperature for 18 h andconcentrated. The residue was purified on silica gel using 0-10% 9.5:0.5methanol:ammonium hydroxide in ethyl acetate to give a yellow solid (0.2g, 0.515 mmol, 66%). MS (LC/MS) R.T.=1.82; [M+H]⁺=389.27.

Step D:(R)—N-(6-(2-Fluoropyridin-3-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine)

To suspension of(S)-1-(6-(2-fluoropyridin-3-yl)pyrimidin-4-yl)-3-((3-hydroxyquinuclidin-3-yl)methyl)thiourea(0.2 g, 0.515 mmol) in N,N-dimethylformamide (20 mL) was added Cs₂CO₃(0.168 g, 0.515 mmol) and DIC (0.241 mL, 1.545 mmol). The suspension wasstirred at room temperature for 18 h, then at 60° C. for 3 h. Themixture was concentrated and the residue was purified on silica gelusing 2-7% 9.5:0.5 methanol:ammonium hydroxide in ethyl acetate toafford(R)—N-(6-(2-fluoropyridin-3-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amineas a pale yellow solid (0.029 g, 0.081 mmol, 16%). ¹H NMR (400 MHz,MeOD) δ ppm 8.83 (1H, d, J=1.26 Hz), 8.55 (1H, ddd, J=9.76, 7.62, 2.01Hz), 8.29 (1H, dt, J=3.02, 1.51 Hz), 7.46 (1H, ddd, J=7.37, 5.10, 1.89Hz), 7.33 (1H, s), 4.06 (1H, d, J=10.32 Hz), 3.76 (1H, d, J=10.32 Hz),3.25 (1H, s), 3.09-3.19 (1H, m), 2.95 (2H, t, J=7.68 Hz), 2.74-2.91 (2H,m), 2.04-2.26 (2H, m), 1.55-1.87 (3H, m). MS (LC/MS) R.T.=1.24;[M+H]⁺=355.28.

Example 331(R)—N-(6-(6-Fluoropyridin-3-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(6-(6-Fluoropyridin-3-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by the method of Example 330, steps A-D, starting from6-fluoropyridin-3-ylboronic acid. ¹H NMR (400 MHz, MeOD) δ ppm 8.88 (1H,d, J=2.52 Hz), 8.82 (1H, s), 8.51-8.60 (1H, m), 7.25 (1H, s), 7.19 (1H,dd, J=8.56, 2.52 Hz), 4.06 (1H, d, J=10.32 Hz), 3.76 (1H, d, J=10.32Hz), 3.22 (1H, s), 3.07-3.14 (1H, m), 2.86-2.98 (2H, m), 2.70-2.87 (2H,m), 2.03-2.20 (2H, m), 1.54-1.87 (3H, m). MS (LC/MS) R.T.=1.21;[M+H]⁺=355.28.

Example 332(R)—N-(6-(5-Fluoropyridin-3-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(R)—N-(6-(5-Fluoropyridin-3-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by the method of Example 330, steps A-D, starting from5-fluoropyridin-3-ylboronic acid. ¹H NMR (400 MHz, MeOD) δ ppm 9.06 (1H,d, J=1.26 Hz), 8.81 (1H, d, J=1.01 Hz), 8.56 (1H, d, J=2.77 Hz), 8.26(1H, dt, J=9.82, 2.27 Hz), 7.30 (1H, br. s.), 4.06 (1H, d, J=10.32 Hz),3.75 (1H, d, J=10.32 Hz), 3.16-3.26 (1H, m), 3.04-3.15 (1H, m),2.86-3.00 (2H, m), 2.81 (2H, t, J=7.30 Hz), 2.01-2.22 (2H, m), 1.52-1.84(3H, m). MS (LC/MS) R.T.=1.20; [M+H]⁺=355.28.

Example 333(R)—N-(6-(1-Methyl-1H-pyrazol-5-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

((R)—N-(6-(1-Methyl-1H-pyrazol-5-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by the method of Example 330, steps A-D, starting from1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. ¹HNMR (500 MHz, MeOD) δ ppm 8.89 (1H, s), 7.54 (1H, d, J=2.14 Hz), 7.28(1H, br. s.), 6.84 (1H, d, J=2.14 Hz), 4.23 (3H, s), 4.18 (1H, d,J=10.99 Hz), 3.98 (1H, d, J=10.68 Hz), 3.81-3.88 (1H, m), 3.72-3.80 (1H,m), 3.53 (1H, t, J=11.75 Hz), 3.34-3.46 (3H, m), 2.53 (1H, br. s.),2.33-2.45 (1H, m), 2.10-2.22 (1H, m), 1.97-2.12 (2H, m). MS (LC/MS)R.T.=1.15; [M+H]⁺=340.29.

Example 334(R)—N-(6-(Pyrazin-2-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 6[Bis(tert-butoxycarbonyl)amino]-4-chloropyrimidine

6-Chloropyrimidin-4-amine (4.1 g, 31.6 mmol) was suspended inacetonitrile. DMAP (0.966 g, 7.91 mmol) and di-tert-butyl dicarbonate(14.74 g, 67.5 mmol) were added and the mixture was stirred at rt for 3days. The solvent was evaporated and the residue was purified by silicagel using 0-15% ethyl acetate in hexanes to give6[bis(tert-butoxycarbonyl)amino]-4-chloropyrimidine as a white solid(6.27 g, 19.01 mmol, 60%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.69(1H, d, J=0.76 Hz), 7.88 (1H, d, J=1.01 Hz), 1.58 (18H, s).

Step B: 6[Bis(tert-butoxycarbonyl)amino]-4-(2′-pyrazinyl)pyrimidine

6[Bis(tert-butoxycarbonyl)amino]-4-chloropyrimidine (1.608 g, 4.88mmol), 2-(tributylstannyl)pyrazine (1.5 g, 4.06 mmol) and Pd(Ph₃P)₄(0.225 g, 0.195 mmol) were combined in toluene, flushed with nitrogenand heated under reflux for 17 h, cooled to rt, concentrated, andpurified on silica gel using 10% ethyl acetate in hexanes, then 20-50%ethyl acetate in hexanes to give a yellow solid (0.94 g, 2.507 mmol,62%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.67 (1H, d, J=1.01 Hz), 9.05(1H, d, J=1.26 Hz), 8.60-8.77 (3H, m), 1.59 (18H, s).

Step C: 6-(Pyrazin-2-yl)pyrimidin-4-amine

Trifluoroacetic acid (2.77 mL, 36.0 mmol) was added to a solution of6[bis(tert-butoxycarbonyl)amino]-4-(2′-pyrazinyl)pyrimidine (1.344 g,3.60 mmol) in dichloromethane at rt. The mixture was stirred at rt for18 h and concentrated. The residue was taken up in ethyl acetate andsaturated NaHCO₃ was carefully added. The organic layer was isolated,dried over Na₂SO₄ and concentrated. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.44(1H, d, J=1.01 Hz), 8.63-8.86 (2H, m), 8.51 (1H, d, J=1.01 Hz), 7.38(1H, d, J=1.26 Hz), 7.17 (2H, br. s.). MS (LC/MS) R.T.=0.37;[M+H]⁺=174.23.

Step D: Dimethyl 6-(pyrazin-2-yl)pyrimidin-4-ylcarbonimidodithioate

To a solution of 6-(pyrazin-2-yl)pyrimidin-4-amine (0.2 g, 1.155 mmol)in DMF was added NaOH (0.115 mL, 2.310 mmol), CS₂ (0.174 mL, 2.89 mmol),NaOH (0.115 mL, 2.310 mmol) and MeI (0.181 mL, 2.89 mmol) at 15 minintervals. Stirring was continued for 1.5 h and the mixture was pouredinto water. The orange solid was separated, washed with water, dried togive a bright yellow solid (0.14 g, 0.505 mmol, 44%). MS (LC/MS)R.T.=3.19; [M+H]⁺=278.19.

Step E:(R)—N-(6-(Pyrazin-2-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

A mixture of dimethyl 6-(pyrazin-2-yl)pyrimidin-4-ylcarbonimidodithioate(0.139 g, 0.501 mmol), Cs₂CO₃ (0.408 g, 1.253 mmol) and(S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.115 g, 0.501mmol) in N,N-dimethylformamide (10 ml) was heated at 80° C. for 3 h. Themixture was concentrated and purified on silica gel using 0-10% 9.5:0.5methanol:ammonium hydroxide in ethyl acetate to give(R)—N-(6-(pyrazin-2-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amineas an off-white solid (0.066 g, 0.194 mmol, 39%). ¹H NMR (400 MHz, MeOD)δ ppm 9.46 (1H, d, J=1.51 Hz), 8.83 (1H, d, J=1.26 Hz), 8.67-8.72 (1H,m), 8.66 (1H, d, J=2.52 Hz), 7.77 (1H, br. s.), 4.05 (1H, d, J=10.32Hz), 3.75 (1H, d, J=10.32 Hz), 3.18-3.26 (1H, m), 3.04-3.15 (1H, m),2.87-3.00 (2H, m), 2.70-2.85 (2H, m), 2.04-2.19 (2H, m), 1.54-1.83 (3H,m). MS (LC/MS) R.T.=0.97; [M+H]⁺=338.29.

Example 335(2R)—N-(6,7-Dimethyl-3-isoquinolinyl)-4′H-spiro[4-azabicyclo[2.2.2]octane-2,5′-[1,3]oxazol]-2′-amine

Step A: 6,7-Dimethylisoquinolin-3-amine

To a solution of methyl 2,2-diethoxyacetimidate (1.50 g, 9.32 mmol) inmethanol (4.9 mL) was added (3,4-dimethylphenyl)methanamine (1.20 g,8.88 mmol) dropwise at ambient temperature. The reaction flask was thenplaced into a preheated oil-bath and stirred at 70° C. for 16 h; afterwhich time, the flask was removed from the oil-bath and allowed to coolto ambient temperature. The volatiles were removed under reducedpressure and the crude material was added dropwise to sulfuric acid(19.7 mL) at ambient temperature. The reaction mixture was stirred for72 h, then the flask was placed into an ice-water bath, diluted withwater (50 mL), and slowly neutralized to pH=10 with sodium hydroxide (10N). As the reaction mixture became basic, an orange precipitate formed.This precipitate was filtered, washed with water, and dried to afford amixture (2:1) of 6,7-dimethylisoquinolin-3-amine and5,6-dimethylisoquinolin-3-amine (1.68 g, 9.75 mmol, >100%). MS (LC/MS)R.T.=0.32; [M+H]⁺=173.13.

Step B: 3-Isothiocyanato-6,7-dimethylisoquinoline

To a solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (1.35 g, 5.81mmol) in dichloromethane (19 mL) at ambient temperature was added amixture (2:1) of 6,7-dimethylisoquinolin-3-amine and5,6-dimethylisoquinolin-3-amine (1.00 g, 5.81 mmol). The reactionmixture was placed into a preheated oil-bath and stirred at 40° C. for18 h, then cooled, concentrated, and purified by silica gelchromatography (10-35% ethyl acetate in hexanes) to afford a mixture(2:1) of 3-isothiocyanato-6,7-dimethylisoquinoline and3-isothiocyanato-5,6-dimethylisoquinoline (186 mg, 0.869 mmol, 15%) as ayellow solid. MS (LC/MS) R.T.=2.06; [M+H]⁺=215.1.

Step C:(2R)—N-(6,7-Dimethyl-3-isoquinolinyl)-4′H-spiro[4-azabicyclo[2.2.2]octane-2,5′-[1,3]oxazol]-2′-amine

To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (99 mg, 0.43mmol) in N,N-dimethylformamide (1.4 mL) was added triethylamine (0.181mL, 1.30 mmol) and a mixture (2:1) of3-isothiocyanato-6,7-dimethylisoquinoline and3-isothiocyanato-5,6-dimethylisoquinoline (93 mg, 0.43 mmol). Thesuspension was placed into a preheated oil-bath and stirred at 80° C.for 2 h and 30 min. N,N′-Diisopropylcarbodiimide (0.270 mL, 1.74 mmol)was then added and the mixture was stirred at 80° C. for 16 h. Themixture was concentrated and purified by silica gel chromatography(0-40% 9:1 methanol:ammonium hydroxide in chloroform) followed bypurification by reverse phase preparatory HPLC (0-40%TFA-methanol-water). The product fractions were combined andconcentrated in vacuo to afford a mixture (2:1) of(2R)—N-(6,7-dimethyl-3-isoquinolinyl)-4′H-spiro[4-azabicyclo[2.2.2]octane-2,5′-[1,3]oxazol]-2′-amineand(2R)—N-(5,6-dimethyl-3-isoquinolinyl)-4′H-spiro[4-azabicyclo[2.2.2]octane-2,5′-[1,3]oxazol]-2′-amineas the trifluoroacetic acid salts. The two regioisomers were separatedusing a Chiralpak AD-H (4.6×250 mm, 5 μm) column with a mobile phaseconsisting of 40% methanol (0.1% DEA) in CO₂, detected at 215 nM, toyield(2R)—N-(6,7-dimethyl-3-isoquinolinyl)-4′H-spiro[4-azabicyclo[2.2.2]octane-2,5′-[1,3]oxazol]-2′-amineas a white solid (5.0 mg, 0.015 mmol, 3% yield). 1H NMR (400 MHz, MeOD)δ ppm 8.87 (1H, s), 7.90 (1H, s), 7.67 (1H, s), 7.50 (1H, s), 3.97 (1H,d, J=10.0 Hz), 3.65 (1H, d, J=10.0 Hz), 3.19-3.27 (1H, m), 3.04-3.17(1H, m), 2.94 (2H, d, J=7.5 Hz), 2.76-2.90 (2H, m), 2.38-2.50 (6H, m),2.11-2.21 (2H, m), 1.57-1.85 (3H, m). MS (LC/MS) R.T.=0.92;[M+H]⁺=337.22.

Example 336(2R)—N-(6-Methyl-1,3-benzoxazol-2-yl)-4′H-spiro[4-azabicyclo[2.2.2]octane-2,5′-[1,3]oxazol]-2′-amine

Step A: 6-Methylbenzo[d]oxazol-2-amine

An oven-dried, round-bottomed flask was charged withdi(1H-imidazol-1-yl)methanimine (1.40 g, 8.69 mmol),2-amino-5-methylphenol (713 mg, 5.79 mmol) and anhydrous THF (20 ml) atambient temperature. The resulting suspension was refluxed under N₂ (g)for 2 h. The solvent was removed in vacuo and the residue was purifiedby silica gel chromatography (0-30% 9:1 methanol:ammoniumhydroxide-chloroform) to afford benzo[d]oxazol-2-amine (792 mg, 5.35mmol, 92% yield), as a grey solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm7.19-7.34 (1H, m), 7.11 (1H, s), 7.01 (1H, d, J=7.8 Hz), 5.60 (2H, br.s.), 2.43 (3H, s). MS (LC/MS) R.T.=0.89; [M+H]⁺=149.09.

Step B: Dimethyl 6-methylbenzo[d]oxazol-2-ylcarbonimidodithioate

To a suspension of 6-methylbenzo[d]oxazol-2-amine (200 mg, 1.35 mmol) inDMF (1.4 mL) was added 20.0 M sodium hydroxide (135 μL, 2.70 mmol). Themixture was allowed to stir for 10 min at room temperature before carbondisulfide was added (203 μL, 3.37 mmol) and the mixture was stirred for10 min. An additional portion of 20.0 M sodium hydroxide (135 μL, 2.70mmol) was added and the mixture was again stirred for 10 min. Finally,iodomethane (203 μL, 3.24 mmol) was added dropwise. After completion ofthe addition, the mixture was stirred for 15 min, at which time avoluminous precipitate had formed. The mixture was poured into water andthe solids were collected by filtration, washed with water, and dried toafford dimethyl 6-methylbenzo[d]oxazol-2-ylcarbonimidodithioate (289 mg,1.14 mmol, 85% yield) as a brown solid. MS (LC/MS) R.T.=1.88;[M+H]⁺=252.95.

Step C:(2R)—N-(6-Methyl-1,3-benzoxazol-2-yl)-4′H-spiro[4-azabicyclo[2.2.2]octane-2,5′-[1,3]oxazol]-2′-amine

A 10 ml vial was charged with (S)-3-(aminomethyl)quinuclidin-3-ol.HCl(38.2 mg, 0.198 mmol, DMF (2 mL), Cs₂CO₃ (129 mg, 0.396 mmol) anddimethyl 6-methylbenzo[d]oxazol-2-ylcarbonimidodithioate (50 mg, 0.198mmol) at ambient temperature. The resulting suspension was stirred for 1h before it was diluted with methanol, and purified by reverse phasepreparatory HPLC (0-100% TFA-methanol-water) to afford(2R)—N-(6-methyl-1,3-benzoxazol-2-yl)-4′H-spiro[4-azabicyclo[2.2.2]octane-2,5′-[1,3]oxazol]-2′-amineas the trifluoroacetic acid salt (55.3 mg, 0.123 mmol, 62% yield) as atan gum. 1H NMR (400 MHz, DMSO-d₆) δ ppm 9.89 (br. s., 1H), 9.15 (br.s., 1H), 7.33 (d, J=8.03 Hz, 1H), 7.31 (s, 1H), 7.06 (d, J=8.78 Hz, 1H),4.00 (d, J=8.0 Hz, 1H), 3.88 (d, J=10.29 Hz, 1H), 3.64-3.80 (m, 2H),3.34-3.44 (m, 1H), 3.20-3.34 (m, 3H), 2.44 (br. s., 1H), 2.40 (s, 3H),2.08-2.20 (m, 1H), 1.80-2.03 (m, 3H). MS (LC/MS) R.T.=0.367,[M+H]⁺=313.2.

Example 337(2R)—N-(6-Methoxy-1,3-benzoxazol-2-yl)-4′H-spiro[4-azabicyclo[2.2.2]octane-2,5′-[1,3]oxazol]-2′-amine

Step A: 6-Methoxybenzo[d]oxazol-2-amine

An oven-dried, round-bottomed flask was charged withdi(1H-imidazol-1-yl)methanimine (500 mg, 3.10 mmol),2-amino-5-methoxyphenol-HCl (365 mg, 2.07 mmol), triethylamine (288 μL,2.07 mmol), and anhydrous THF (20 ml) at ambient temperature. Theresulting suspension was refluxed under N₂ (g) for 20 h to give completeconversion based on LC/MS. The solvent was removed in vacuo and theresidue was purified by silica gel chromatography (30-80% ethyl acetatein hexanes) to afford 6-methoxybenzo[d]oxazol-2-amine (307 mg, 1.87mmol, 90% yield), as a brown solid. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm7.28 (1H, d, J=9.5 Hz), 6.92 (1H, d, J=2.4 Hz), 6.80 (1H, dd, J=8.5, 2.1Hz), 5.28 (2H, br. s.). MS (LC/MS) R.T.=1.51; [M+H]⁺=165.00.

Step B: Dimethyl 6-methoxybenzo[d]oxazol-2-ylcarbonimidodithioate

To a suspension of 6-methoxybenzo[d]oxazol-2-amine (238 mg, 1.45 mmol)in DMF (2.0 mL) was added 20.0 M sodium hydroxide (145 μL, 2.90 mmol).The mixture was allowed to stir for 10 min at room temperature beforecarbon disulfide was added (219 μL, 3.62 mmol) and the mixture wasstirred for 10 min. An additional portion of 20.0 M sodium hydroxide(145 μL, 2.90 mmol) was added and the mixture was again stirred for 10min. Finally, iodomethane (218 μL, 3.48 mmol) was added dropwise. Themixture was stirred for an additional 15 min, by which time a voluminousprecipitate had formed. The mixture was poured into water and the solidswere collected by filtration, washed with water, and dried to afforddimethyl 6-methoxybenzo[d]oxazol-2-ylcarbonimidodithioate. The materialwas used without characterization.

Step C:(2R)—N-(6-Methoxy-1,3-benzoxazol-2-yl)-4′H-spiro[4-azabicyclo[2.2.2]octane-2,5′-[1,3]oxazol]-2′-amine

A 10 ml vial was charged with (S)-3-(aminomethyl)quinuclidin-3-ol.HCl(24.5 mg, 0.127 mmol), DMF (2 mL), Cs₂CO₃ (83 mg, 0.25 mmol), anddimethyl 6-methoxybenzo[d]oxazol-2-ylcarbonimidodithioate (34 mg, 0.13mmol) at ambient temperature. The resulting suspension was stirred atambient temperature for 1 h, diluted with methanol and purified byreverse phase preparatory HPLC (0-100% TFA-methanol-water) to afford(R)—N-(6-methoxybenzo[d]oxazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amineas the trifluoroacetic acid salt (7.2 mg, 0.014 mmol, 11% yield) as atan gum. 1H NMR (400 MHz, DMSO-d₆) δ ppm 9.95 (br. s., 1H), 9.10 (br.s., 1H), 7.34 (d, J=8.78 Hz, 1H), 7.17 (d, J=2.51 Hz, 1H), 6.84 (dd,J=8.53, 2.51 Hz, 1H), 3.99 (d, J=10.54 Hz, 1H), 3.87 (d, J=10.54 Hz,1H), 3.79 (s, 3H), 3.63-3.78 (m, 2H), 3.34-3.44 (m, 1H), 3.20-3.32 (m,3H), 2.43 (m, 1H), 2.09-2.19 (m, 1H), 1.91-2.02 (m, 1H), 1.80-1.91 (m,2H). MS (LC/MS) R.T.=0.867, [M+H]⁺=329.28.

Examples 338A and 338B(R)—N-(5-chloroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(A) and(R)—N-(7-chloroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(B)

Step A: N-(3-Chlorobenzyl)-2,2-diethoxyacetimidamide

In a nitrogen-flushed sealed tube was placed methyl2,2-diethoxyacetimidate (2 g, 12.41 mmol) in methanol (6 mL) and(3-chlorophenyl)methanamine (1.444 mL, 11.82 mmol). The tube was cappedand heated to 70° C. After 18 hours, the reaction was cooled to roomtemperature and the reaction was concentrated to yieldN-(3-chlorobenzyl)-2,2-diethoxyacetimidamidea (2.3 grams, 8.5 mmol, 71%)as a yellow oil.

1H NMR (400 MHz, DMSO-d₆) δ ppm 7.14-7.50 (m, 4H) 4.80 (br. s., 1H) 4.29(br. s., 2H) 4.05 (q, J=7.11 Hz, 1H) 3.40-3.73 (m, 4H) 2.01 (s, 1H)1.05-1.29 (m, 6H) LC/MS RT=1.12 mins, [M+H]=271.09.

Step B: 5- and 7-Chloro-isoquinoline-3-amine

In a flask was placed N-(3-chlorobenzyl)-2,2-diethoxyacetimidamide (1.9g, 7.02 mmol) and sulfuric acid (14 mL, 263 mmol). This was stirred atroom temperature for 24 hours. The reaction was then neutralized to pH 9using 10 N NaOH. The resulting precipitate was dissolved indichloromethane and the water layer was washed with dichloromethane. Theorganic layers were combined and concentrated to give the aboveregioisomers (1.1 grams, 6.1 mmol, 88%) in a 2:1 ratio of7-chloroisoquinolin-3-amine to 5-chloroisoquinolin-3-amine. Thisregioisomer mixture is carried on without further separation. 1H NMR(400 MHz, DMSO-d₆) δ ppm 8.89 (s, 1H) 8.81 (s, 2H) 7.90 (d, J=2.26 Hz,2H) 7.82 (d, J=8.28 Hz, 1H) 7.65 (dd, J=7.28, 1.00 Hz, 1H) 7.58 (d,J=9.03 Hz, 2H) 7.44 (dd, J=9.03, 2.26 Hz, 2H) 7.07-7.19 (m, 1H) 6.83 (s,1H) 6.64 (s, 2H) 6.28 (s, 2H) 6.05 (s, 4H) LC/MS R.T=0.955 mins,[M+H]=181.03.

Step C: 5- and 7-Chloro-3-isothiocyanato-isoquinoline

In a vial was placed7-chloroisoquinolin-3-amine/5-chloroisoquinolin-3-amine (550 mg, 3.08mmol) and 1,1′-thiocarbonyldipyridin-2(1H)-one (858 mg, 3.70 mmol) indichloromethane (10 mL). The reaction was stirred at room temperature.After 18 hours, the reaction was purified on a silica gel cartridge,eluting in 50% ethyl acetate in hexanes to give a mixture of7-chloro-3-isothiocyanatoisoquinoline and5-chloro-3-isothiocyanatoisoquinoline (400 mg, 1.8 mmol, 58%) which wasused immediately in the next reaction. LC/MS RT=3.808 mins [M+H]=221.0.

Step D:(R)—N-(5-chloroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amineand(R)—N-(7-chloroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

In a vial was placed7-chloro-3-isothiocyanatoisoquinoline/5-chloro-3-isothiocyanatoisquinoline(400 mg, 1.813 mmol) and (S)-3-(aminomethyl)quinuclidin-3-ol (340 mg,2.175 mmol) in DMF (8 mL). To this was added cesium carbonate (1417 mg,4.35 mmol). The reaction was allowed to stir at 50 C for 1 hour and thenN,N′-diisopropylcarbodiimide (0.847 mL, 5.44 mmol) was added to thereaction and the reaction was allowed to stir overnight. After 18 hoursthe reaction was poured into water and chloroform. The organic wascollected, concentrated, and purified on the Biotage eluting in5-40%(10% NH4OH/Methanol) in chloroform. The product regioisomers werecollected and separated by preparative SFC to give(R)—N-(5-chloroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(12.5 mg) as a light yellow solid. 1H NMR (400 MHz, DMSO-d₆) δ ppm 9.14(s, 1H) 8.67 (br. s., 1H) 8.03 (d, J=8.28 Hz, 1H) 7.82 (d, J=7.28 Hz,1H) 7.41 (t, J=8.03 Hz, 1H) 3.90 (br. s., 1H) 3.63 (br. s., 1H)2.91-3.16 (m, 2H) 2.65-2.92 (m, 4H) 1.85-2.19 (m, 2H) 1.16-1.81 (m, 4H)LC/MS RT=1.578 mins [M+H]=343.08, and(R)—N-(7-chloroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(54.9 mg) was isolated as a light yellow solid. 1H NMR (400 MHz,DMSO-d₆) δ ppm 9.06 (s, 1H) 8.43-8.93 (m, 1H) 8.13 (br. s., 1H) 7.82(br. s., 1H) 7.61 (d, J=8.28 Hz, 1H) 3.89 (br. s., 1H) 3.61 (br. s., 1H)3.31 (br. s., 1H) 2.90-3.18 (m, 2H) 2.62-2.95 (m, 4H) 1.82-2.13 (m, 2H)1.34-1.80 (m, 3H) LC/MS R.T=0.898 mins[M+H]=343.32.

Example 339(R)—N-(6-Chlorothiazolo[4,5-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: N-(3,5-Dichloropyridin-2-ylcarbamothioyl)benzamide

To 3,5-dichloropyridin-2-amine (3.87 g, 23.73 mmol) in acetone (20 mL)was added benzoyl isothiocyanate (3.2 mL, 23.73 mmol). The mixture wasstirred at ambient temperature for 1 h, and the resultant precipitatewas collected by filtration (3.89 g). The filtrate was returned to thereaction flask and heated to reflux 1 h. At this time, the reaction hadgone dry. The solids were suspended in acetone and collected byfiltration to give 2.24 g. ofN-(3,5-dichloropyridin-2-ylcarbamothioyl)benzamide (5.93 g, 18.18 mmol,77% yield). ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 12.78 (br. s., 1H) 9.25(br. s., 1H) 8.46 (br. s., 1H) 7.94 (d, J=7.63 Hz, 2H) 7.88 (d, J=2.44Hz, 1H) 7.69 (t, J=7.48 Hz, 1H) 7.58 (t, J=7.78 Hz, 2H).

Step B: N-(6-Chlorothiazolo[4,5-b]pyridin-2-yl)benzamide

To N-(3,5-dichloropyridin-2-ylcarbamothioyl)benzamide (5.2 g, 16 mmol)in NMP (40 mL) was added sodium methoxide (1.73 g, 32.0 mmol). Themixture was heated in a 120° C. oil bath for 4 h, cooled to ambienttemperature and poured into water. The solids were collected byfiltration and purified on by silica gel chromatography (0-5% (9:1MeOH:NH₄OH)/chloroform) to giveN-(6-chlorothiazolo[4,5-b]pyridin-2-yl)benzamide (364 mg, 1.256 mmol,7.85% yield).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.16 (br. s., 1H) 8.48-8.58 (m, 2H)8.13-8.23 (m, 2H) 7.61-7.69 (m, 1H) 7.56 (t, J=7.53 Hz, 2H). MS (LC/MS)R.T.=2.8; [M+H]⁺=290.1.

Step C: 6-Chlorothiazolo[4,5-b]pyridin-2-amine

N-(6-Chlorothiazolo[4,5-b]pyridin-2-yl)benzamide (364 mg, 1.256 mmol) inH₂SO₄ (4 ml, 75 mmol) was heated to 120° C. for 30 minutes, cooled toambient temperature, basified with 10N NaOH and the resultant solidswere collected by filtration to afford6-chlorothiazolo[4,5-b]pyridin-2-amine (148 mg, 0.797 mmol, 63.5%yield)¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.19-8.24 (m, 2H) 8.09 (br. s.,2H).

Step D: Dimethyl 6-chlorothiazolo[4,5-b]pyridin-2-ylcarbonimidodithioate

6-Chlorothiazolo[4,5-b]pyridin-2-amine (148 mg, 0.797 mmol) wassuspended in DMF (1 ml) and 16 N NaOH (0.100 ml, 1.595 mmol) was added.The mixture was stirred 10 min at ambient temperature, at which time,CS₂ (0.120 ml, 1.993 mmol) was added. The mixture was stirred for afurther 10 min at ambient temperature and 16 N NaOH (0.100 ml, 1.595mmol) was added. The mixture was stirred 10 min at ambient temperature,at which time, iodomethane (0.120 ml, 1.913 mmol) was added. After 15minutes, the mixture was diluted with water and the resultant solidswere collected by filtration. The filtrate was extracted thrice withchloroform and dried over sodium sulfate. The crude mixture was purifiedby silica gel chromatography (2-50% EtOAc/CHCl₃) to afford dimethyl6-chlorothiazolo[4,5-b]pyridin-2-ylcarbonimidodithioate (50 mg, 0.173mmol, 21.64% yield). ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.57 (s, 1H)8.09 (s, 1H) 2.66 (s, 6H).

Step E:(R)—N-(6-Chlorothiazolo[4,5-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Dimethyl 6-chlorothiazolo[4,5-b]pyridin-2-ylcarbonimidodithioate (50 mg,0.17 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol, 2 HCl (40 mg, 0.17mmol) and cesium carbonate (112 mg, 0.35 mmol) were suspended in DMF (1mL) and heated in an open flask on a 100° C. oil bath. After 2.5 h, themixture was cooled to ambient temperature and poured into water. Themixture was extracted with chloroform 4×, dried over sodium sulfate,filtered, and concentrated to residue. The crude residue was purified bysilica gel chromatography 5-40% (9:1 MeOH/NH₄OH)/CHCl₃ to afford(R)—N-(6-chlorothiazolo[4,5-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(20 mg, 0.056 mmol, 32.5% yield) as a white powder.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.31 (d, J=2.51 Hz, 1H) 7.93 (d,J=2.26 Hz, 1H) 3.99 (d, J=10.04 Hz, 1H) 3.67 (d, J=10.04 Hz, 1H)3.20-3.39 (m, 2H) 2.86-3.05 (m, 3H) 2.67-2.87 (m, 2H) 2.03-2.19 (m, 2H)1.74 (ddd, J=13.87, 9.35, 4.64 Hz, 1H) 1.44-1.65 (m, 2H). MS (LC/MS)R.T.=1.49; [M+H]⁺=350.2.

Example 340(R)—N-(5-fluorothiazolo[5,4-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 5-Fluorothiazolo[5,4-b]pyridin-2-amine

6-Fluoropyridin-3-amine (4 g, 35.7 mmol) was added to a 3-neck flaskcontaining a mechanically stirred suspension of potassium rhodanate(27.7 g, 285 mmol) in acetic acid (89 mL) at 0° C. The flask was thenfitted with an addition funnel charged with bromine (5.70 mL, 111 mmol)in acetic acid (29.7 mL). The bromine solution was added over 30 min andthe solution turned into a viscous yellow mixture. After bromineaddition was complete, the reaction mixture was allowed to warm toambient temperature and stirred for 16 h. Water (30 mL) was added andthe mixture was heated to 85° C. for 20 min before the solids werefiltered and washed with water and methanol to give5-fluorothiazolo[5,4-b]pyridin-2-amine (4.18 g, 24.71 mmol, 69.2% yield)as a yellow solid.

Step B: Dimethyl 5-fluorothiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate

5-Fluorothiazolo[5,4-b]pyridin-2-amine (2.0 g, 11.8 mmol) was reactedaccording to the method of Example 339, STEP D to provide dimethyl5-fluorothiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate (2.17 g, 67%yield) as a yellow solid. ¹H NMR (500 MHz, chloroform-d) δ ppm 8.14 (dd,J=8.55, 7.02 Hz, 1H) 6.98 (dd, J=8.70, 1.98 Hz, 1H) 2.63 (s, 6H).

Step C:(R)—N-(5-Fluorothiazolo[5,4-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Dimethyl 5-fluorothiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate (100mg, 0.37 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol, 2 HCl (84 mg, 0.37mmol) and cesium carbonate (238 mg, 0.73 mmol) were suspended in DMF (2mL) and heated in an open flask in a 100° C. oil bath. After 2.5 h, themixture was cooled to ambient temperature and poured into water. Themixture was extracted with chloroform 4×, dried over sodium sulfate,filtered, and concentrated. The crude residue was purified by silica gelchromatography 5-40% (9:1 MeOH/NH₄OH)/CHCl₃ to afford((R)—N-(5-fluorothiazolo[5,4-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(85 mg, 66% yield) as a white powder. ¹H NMR (400 MHz, CHLOROFORM-d) δppm 9.17 (br. s., 1H) 7.89 (dd, J=8.66, 6.90 Hz, 1H) 6.91 (dd, J=8.53,2.01 Hz, 1H) 4.04 (d, J=9.54 Hz, 1H) 3.73 (d, J=9.54 Hz, 1H) 3.43 (dd,J=14.93, 1.63 Hz, 1H) 3.08 (dd, J=15.06, 1.76 Hz, 1H) 2.84-3.05 (m, 4H)2.16-2.28 (m, 2H) 1.75-1.87 (m, 1H) 1.53-1.70 (m, 2H). MS (LC/MS)R.T.=1.37; [M+H]⁺=334.2.

Example 341(R)—N-(6-methylthiazolo[5,4-b]pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 3-Bromo-5-methylpyrazin-2-amine

To a suspension of 5-methylpyrazin-2-amine (1.09 g, 10 mmol) inchloroform (100 mL) was added pyridine (0.85 mL, 10.5 mmol). The mixturewas stirred in a foil-wrapped flask fitted with an addition funnel, anda solution of bromine (0.54 mL, 10.5 mmol) in chloroform (10 mL) wasadded dropwise over 10 min. The mixture was allowed to react anadditional 20 minutes after addition was complete and then poured into aseparatory funnel containing 10 mL water. The phases were separated andthe organics washed again with water, dried over sodium sulfate,filtered and concentrated in vacuo. The resulting red oil was purifiedby silica gel chromatography with 12-100% EtOAc/hexanes. The major UVactive peak was collected to give 3-bromo-5-methylpyrazin-2-amine (1.06g, 5.64 mmol, 56.4% yield) as a cream-colored solid. ¹H NMR (500 MHz,DMSO-d6) δ ppm 7.85 (s, 1H) 6.42 (br. s., 2H) 2.25 (s, 3H). MS (LC/MS)R.T.=0.93; [M+H]⁺=189.9.

Step B: Ethyl 6-methylthiazolo[5,4-b]pyrazin-2-ylcarbamate

To 3-bromo-5-methylpyrazin-2-amine (850 mg, 4.52 mmol) was addedethoxycarbonyl isothiocyanate (0.51 mL, 4.52 mmol) followed by toluene(1 mL). The mixture was placed in a preheated 100° C. oil bath, andwithin a minute, all the solids had dissolved. After 15 min, all hadseized to a solid mass. After an additional 15 minutes, methanol (˜5 mL)was added and the mixture refluxed to digest the solids. The mixture wascooled to rt after 5 minutes and the solids collected by filtration,washing with methanol to give ethyl6-methylthiazolo[5,4-b]pyrazin-2-ylcarbamate (680 mg, 2.85 mmol, 63.1%yield). ¹H NMR (400 MHz, DMSO-d6) 8 ppm 12.48 (br. s., 1H) 8.48 (s, 1H)4.30 (q, J=7.03 Hz, 2H) 2.56-2.65 (m, 3H) 1.31 (t, J=7.15 Hz, 3H). MS(LC/MS) R.T.=2.10; [M+H]⁺=239.17.

Step C: 6-Methylthiazolo[5,4-b]pyrazin-2-amine

Ethyl 6-methylthiazolo[5,4-b]pyrazin-2-ylcarbamate (660 mg, 2.77 mmol)was suspended in 1N NaOH (15 ml, 15.00 mmol) and heated in a 100° C. oilbath for 4 h and cooled to ambient temperature. The mixture wasacidified with 1N HCl and the resulting precipitate was filtered off andwashed with ether, affording 6-methylthiazolo[5,4-b]pyrazin-2-amine (233mg, 1.402 mmol, 50.6% yield) as a yellow powder. ¹H NMR (500 MHz,DMSO-d6) δ ppm 8.26 (s, 2H) 8.12 (s, 1H) 2.43 (s, 3H). MS (LC/MS)R.T.=0.66; [M+H]⁺=167.0.

Step D: Dimethyl 6-methylthiazolo[5,4-b]pyrazin-2-ylcarbonimidodithioate

6-Methylthiazolo[5,4-b]pyrazin-2-amine (0.22 g, 1.32 mmol) was reactedaccording to the method of Example 339, STEP D to provide dimethyl6-methylthiazolo[5,4-b]pyrazin-2-ylcarbonimidodithioate (265 mg, 59%yield) as a yellow solid. ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.45 (s,1H) 2.66-2.68 (m, 9H).

Step E:(R)—N-(6-Methylthiazolo[5,4-b]pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Dimethyl 6-methylthiazolo[5,4-b]pyrazin-2-ylcarbonimidodithioate (150mg, 0.56 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol, 2 HCl (140 mg, 0.61mmol) and cesium carbonate (450 mg, 1.39 mmol) were suspended in DMF (3mL) and heated in an open flask in a 100° C. oil bath. After 2.5 h, themixture was cooled to ambient temperature and poured into water. Themixture was extracted with chloroform 4×, dried over sodium sulfate,filtered, and concentrated to residue. The crude residue was purified bysilica gel chromatography 5-40% (9:1 MeOH/NH₄OH)/CHCl₃ to afford(R)—N-(6-methylthiazolo[5,4-b]pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(51 mg, 27% yield) as a white powder. ¹H NMR (400 MHz, CHLOROFORM-d) δppm 9.45 (br. s., 1H) 8.26 (s, 1H) 4.02 (d, J=9.79 Hz, 1H) 3.69 (d,J=9.79 Hz, 1H) 3.39 (dd, J=14.93, 1.63 Hz, 1H) 2.72-3.06 (m, 5H) 2.60(s, 3H) 2.11-2.22 (m, 2H) 1.70-1.82 (m, 1H) 1.49-1.64 (m, 2H). MS(LC/MS) R.T.=1.15; [M+H]⁺=331.2.

Example 342(R)—N-(6,7-dimethoxyisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: N-(3,4-Dimethoxybenzyl)-2,2-diethoxyacetimidamide

A mixture of methyl 2,2-diethoxyacetimidate (294 mg, 1.824 mmol),(3,4-dimethoxyphenyl)methanamine (312 mg, 1.866 mmol), and MeOH (1.5 mL)was heated with stirring in an oil bath at 70° C. for 2 hrs and allowedto cool to room temperature. The volatile components were removed invacuo. The residue was carried on without further purification. LCMS RT0.96 min, MH⁺=297.2, 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.79-6.93 (3H,m), 4.94 (1H, s), 4.41 (2H, s), 3.84-3.90 (6H, m), 3.52-3.70 (4H, m),1.19-1.28 (6H, m).

Step B: 6,7-Dimethoxyisoquinolin-3-amine

To N-(3,4-dimethoxybenzyl)-2,2-diethoxyacetimidamide (541 mg, 1.825mmol) was added sulfuric acid (0.95 mL, 1.825 mmol) was added. Aftercooling, the reaction was allowed to stand at ambient temperatureovernight. It was added dropwise to ice, then the resulting solution wasneutralized with conc. NaOH, and the aqueous phase was twice extractedwith ethyl acetate. The combined ethyl acetate fractions were dried overmagnesium sulfate. The drying agent was filtered off and the solventevaporated. The residue was purified by column chromatography in 5%methanol/ethyl acetate, collecting the main component. Yield 105.7 mgbrown solid (28%).

LCMS RT 0.72 min, MH⁺=205.1; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.59(1H, s), 7.03 (1H, s), 6.80 (1H, s), 6.70 (1H, s), 4.00 (3H, s), 3.98(3H, s)

Step C: 3-Isothiocyanato-6,7-dimethoxyisoquinoline

To a stirring solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (124.6mg, 0.536 mmol) in dichloromethane (3 mL) was added a suspension of6,7-dimethoxyisoquinolin-3-amine (105 mg, 0.514 mmol) in dichloromethane(5 mL). The reaction mixture was applied directly to a Biotage column in15-25% ethyl acetate/hexane followed by 100% ethyl acetate to give3-isothiocyanato-6,7-dimethoxyisoquinoline as a white solid. Yield 69.4mg (55%) NMR 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.81 (1H, s), 7.31(1H, s), 7.16 (1H, s), 6.98 (1H, s), 3.99 (6H, s).

Step D:(R)—N-(6,7-dimethoxyisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To a stirring suspension of(S)-3-(ammoniomethyl)-3-hydroxy-1-azoniabicyclo[2.2.2]octane chloride(73 mg, 0.319 mmol) and cesium carbonate (221 mg, 0.678 mmol) in DMF (5mL) was added a solution of 3-isothiocyanato-6,7-dimethoxyisoquinoline(69 mg, 0.280 mmol) in DMF (1.5 mL) and the reaction mixture was allowedto stir at room temperature for 3 days. To the solution was then added asolution of N,N′-methanediylidenedipropan-2-amine (69 mg, 0.547 mmol) inDMF (0.4 mL) and the reaction was allowed to stand at room temperaturefor 14 days. Another 69 mg di-isopropylcarbodiimide was added in ˜0.4 mLacetonitrile and the reaction was allowed to stand for 1 more day, thenit was evaporated in vacuo and the residue subjected to preparative HPLCto yield(R)—N-(6,7-dimethoxyisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine20.9 mg. (8%) LCMS RT 0.98 min, MH⁺=403.2 1H NMR (500 MHz, CHLOROFORM-d)δ ppm 8.73 (1H, s), 7.28 (1H, s), 7.09 (1H, s), 6.96 (1H, s), 4.01 (3H,s), 4.00 (3H, s), 3.96 (1H, d, J=8.5 Hz), 3.63 (1H, d, J=9.2 Hz), 3.39(1H, d, J=15.0 Hz), 2.79-3.10 (5H, m), 2.24 (1H, br. s.), 2.15 (1H, br.s.), 1.75 (1H, dddd, J=13.9, 9.3, 4.7, 4.4 Hz), 1.59-1.68 (1H, m),1.48-1.59 (1H, m).

Example 343(R)—N-(5,6,7,8-Tetrahydroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 5,6,7,8-Tetrahydroisoquinolin-3-amine

A mixture of isoquinolin-3-amine (239 mg, 1.66 mmol), platinum(IV)oxide(28 mg, 0.123 mmol), and TFA (6 mL) was hydrogenated in the Parrapparatus for 3 hrs. The reaction mixture was filtered with the aid ofethyl acetate. The filtrate was evaporated in vacuo and the residue waspartitioned between 10% aqueous sodium carbonate and ethyl acetate. Thelayers were separated, the aqueous phase was washed again with ethylacetate, and the combined organic layers were washed with brine anddried over magnesium sulfate. The drying agent was filtered off and thesolvent evaporated. The material was purified by column chromatographyin ethyl acetate to give 139.8 mg (57%)5,6,7,8-tetrahydroisoquinolin-3-amine as a yellow-white solid. LCMS RT0.75 min, MH⁺=149.1 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.78 (1H, s),6.26 (1H, s), 4.29 (2H, br. s.), 2.64 (4H, ddd, J=10.6, 5.8, 5.5 Hz),1.64-1.87 (4H, m).

Step B: 3-Isothiocyanato-5,6,7,8-tetrahydroisoquinoline

To a stirring solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (222 mg,0.956 mmol) in dichloromethane (5 mL) was added a solution of5,6,7,8-tetrahydroisoquinolin-3-amine (139 mg, 0.938 mmol) indichloromethane (1.5 mL) and the resulting solution was stirred at roomtemperature overnight. e reaction mixture was applied directly to aBiotage column in 20-25% ethyl acetate/hexane, collecting the firstmajor peak. Yield 141.8 mg (79%)3-isothiocyanato-5,6,7,8-tetrahydroisoquinoline. NMR 1H NMR (500 MHz,CHLOROFORM-d) δ ppm 8.10 (1H, s), 6.84 (1H, s), 2.74 (4H, t, J=6.3 Hz),1.81 (4H, dd, J=4.0, 2.7 Hz).

Step C:(S)-1-((3-Hydroxyquinuclidin-3-yl)methyl)-3-(5,6,7,8-tetrahydroisoquinolin-3-yl)thio-urea

To a stirring suspension of(S)-3-(ammoniomethyl)-3-hydroxy-1-azoniabicyclo[2.2.2]octane chloride(183 mg, 0.799 mmol) and cesium carbonate (550 mg, 1.688 mmol) in DMF(10 mL) was added a solution of3-isothiocyanato-5,6,7,8-tetrahydroisoquinoline (141 mg, 0.741 mmol) inDMF (2 mL) and the reaction mixture was stirred at room temperature for10 days. Then the solvent was removed in vacuo and the residue was takenup in methanol and purified on a silica gel column in 1% NH₄OH/9%MeOH/90% CHCl₃ followed by purification via preparative HPLC. Theisolated product was partitioned between aqueous sodium carbonate andethyl acetate. The aqueous phase was washed again with ethyl acetate andthe combined organic phases were washed with brine, dried over magnesiumsulfate, filtered and the solvent evaporated. The residue wasre-purified on a silica gel column in 1% NH₄OH/9% MeOH/90% CHCl₃ to give(S)-1-((3-hydroxyquinuclidin-3-yl)methyl)-3-(5,6,7,8-tetrahydroisoquinolin-3-yl)thio-urea,yield 98 mg (35%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 12.02 (1H, brs), 8.23 (1H, br s), 7.88 (1H, s), 6.41 (1H, s), 4.08 (1H, dd), 3.89(1H, dd), 3.46 (2H, s), 3.05-2.80 (5H, m), 2.69 (4H, dt), 2.10 (1H, brs), 1.93 (1H, br s), 1.85 (1H, m), 1.77 (4H, m), 1.66 (1H, m), 1.45 (1H,m); LCMS RT 1.11 min, MH⁺=447.1.

Step D:(R)—N-(5,6,7,8-Tetrahydroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo-[2.2.2]octan]-2-amine

To a solution of(S)-1-((3-hydroxyquinuclidin-3-yl)methyl)-3-(5,6,7,8-tetrahydroisoquinolin-3-yl)thiourea(98 mg, 0.283 mmol) in DMF (2 mL) was added a solution ofN,N′-methanediylidenedipropan-2-amine (41 mg, 0.325 mmol) in DMF (0.4mL) and the resulting solution was allowed to stand at room temperaturefor 7 days.

Another 53 mg di-isopropylcarbodiimide was added in ˜0.4 mL acetonitrileand the reaction was allowed to stand for 1 more day. The reactionmixture was then evaporated in vacuo and subjected to preparative HPLCfollowed by silica gel chromatography in 1% NH₄OH/9% MeOH/90% CHCl₃ togive(R)—N-(5,6,7,8-tetrahydroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo-[2.2.2]octan]-2-amine,yield 6.4 mg. (7%).

LCMS RT 0.80 min, MH⁺=313.2; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.91(1H, s), 6.75-6.95 (1H, m), 3.91 (1H, d, J=9.5 Hz), 3.60 (1H, d, J=9.5Hz), 3.38 (1H, s), 2.93-3.13 (4H, m), 2.86-2.93 (2H, m), 2.69 (4H, td,J=11.4, 6.1 Hz), 2.21-2.32 (1H, m), 2.16 (1H, br. s.), 1.72-1.85 (5H,m), 1.64 (1H, dd, J=7.2, 4.4 Hz), 1.56 (1H, dt, J=7.0, 2.6 Hz).

Example 344(R)—N-(6-Chloro-7-methoxyisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: N-(4-Chloro-3-methoxybenzyl)-2,2-diethoxyacetimidamide

To a mixture of (4-chloro-3-methoxyphenyl)methanamine (392 mg, 2.284mmol) (as the hydrochloride salt), Hunig's Base (0.5 mL, 2.86 mmol), andMeOH (2 mL) was added a solution of methyl 2,2-diethoxyacetimidate (295mg, 1.83 mmol) in MeOH (1 mL) and the resulting mixture was heated withstirring in an oil bath at 70° C. for 2 hrs and allowed to cool to roomtemperature over 3 days. The solvent was removed in vacuo and theresidue was used without further purification.

Step B: 6-Chloro-7-methoxyisoquinolin-3-amine

To cold (0° C.) sulfuric acid (0.071 mL, 1.330 mmol) was added graduallya suspension of N-(4-chloro-3-methoxybenzyl)-2,2-diethoxyacetimidamide(400 mg, 1.330 mmol) in dichloromethane (5 mL) and the resulting mixturewas allowed to warm up to room temperature overnight. The reactionmixture was then added slowly to crushed ice, then the mixture was madestrongly basic by adding conc. NaOH solution and the organic componentswere extracted into ethyl acetate. The organic fraction was dried overmagnesium sulfate, filtered, and the solvent was evaporated. The residuewas subjected to silica gel chromatography in ethyl acetate to give110.8 mg. (40%) 6-chloro-7-methoxyisoquinolin-3-amine. LCMS RT 0.95 min,MH⁺=209.0, 211.0; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.66 (1H, s),7.78 (1H, s), 6.83 (1H, s), 6.63 (1H, s), 4.36-4.58 (2H, m), 3.99 (3H,s).

Step C: 6-Chloro-3-isothiocyanato-7-methoxyisoquinoline

To a stirring solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (142 mg,0.611 mmol) in dichloromethane (5 mL) was added a suspension of6-chloro-7-methoxyisoquinolin-3-amine (110 mg, 0.527 mmol) indichloromethane (5.00 mL) and the reaction mixture was stirred at roomtemperature overnight. The reaction mixture was applied directly to asilica gel column in 10% ethyl acetate/hexane to yield 106 mg (80%)6-Chloro-3-isothiocyanato-7-methoxyisoquinoline. 1H NMR (500 MHz,CHLOROFORM-d) δ ppm 8.90 (1H, s), 7.99 (1H, s), 7.36 (1H, s), 7.08 (1H,s), 4.05 (3H, s).

Step D:(S)-1-(6-Chloro-7-methoxyisoquinolin-3-yl)-3-((3-hydroxyquinuclidin-3-yl)methyl)thiourea

To a stirring suspension of(S)-3-(ammoniomethyl)-3-hydroxy-1-azoniabicyclo[2.2.2]octane chloride(111 mg, 0.484 mmol) in DMF (3 mL) was added Hunig's Base (0.5 mL, 2.86mmol) and the resulting mixture was stirred at room temperature for 35minutes. Then was added a suspension of6-chloro-3-isothiocyanato-7-methoxyisoquinoline (106 mg, 0.423 mmol) inDMF (3 mL) and the reaction mixture was allowed to stir at roomtemperature overnight. The solvent was evaporated in vacuo and theresidue subjected to a silica gel column in 1% NH₄OH/9% MeOH/90% CHCl₃

to give 140.3 mg (82%) as a white solid,(S)-1-(6-chloro-7-methoxyisoquinolin-3-yl)-343-hydroxyquinuclidin-3-yl)methyl)thiourea.LCMS RT 1.28 min, MH⁺=407.1, 409.0, 1H NMR (500 MHz, CHLOROFORM-d) δ ppm11.85 (1H, t, J=5.2 Hz), 9.15 (1H, br. s.), 8.63 (1H, s), 7.76 (1H, s),6.92 (1H, s), 6.89 (1H, s), 4.14 (1H, dd, J=13.9, 5.6 Hz), 3.99 (2H, s),3.90 (1H, dd, J=14.0, 5.2 Hz), 3.46 (3H, s), 2.89-3.01 (2H, m),2.75-2.88 (3H, m), 2.03-2.15 (1H, m), 1.89-1.96 (1H, m), 1.77-1.88 (1H,m), 1.63 (1H, ddd, J=13.4, 6.1, 3.4 Hz), 1.32-1.45 (1H, m).

Step E:(R)—N-(6-Chloro-7-methoxyisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To a solution of(S)-1-(6-chloro-7-methoxyisoquinolin-3-yl)-3-((3-hydroxyquinuclidin-3-yl)methyl)thiourea(140 mg, 0.344 mmol) in DMF (2.5 mL) was added a solution ofN,N′-methanediylidenedipropan-2-amine (101 mg, 0.800 mmol) in DMF (0.5mL) and the resulting mixture was allowed to stand at room temperaturefor 10 days. The solvent was then evaporated in vacuo. The residue wasdissolved in ˜5 mL MeOH (some white solid was filtered off, 09) andsubjected to preparative HPLC purification followed by silica gelchromatography in 1% NH₄OH/9% MeOH/90% CHCl₃ to give 31 mg (24%)(R)—N-(6-chloro-7-methoxyisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine.

LCMS RT 1.04 min, MH⁺=373.2, 375.2 1H NMR (500 MHz, MeOD) δ ppm8.78-8.89 (1H, m), 7.90-8.01 (1H, m), 7.14-7.23 (1H, m), 4.01 (3H, s),3.95-3.99 (1H, m), 3.62-3.71 (1H, m), 3.19-3.25 (1H, m), 3.06-3.13 (1H,m), 2.90-3.00 (2H, m), 2.76-2.89 (2H, m), 2.10-2.21 (2H, m), 1.69-1.83(2H, m), 1.56-1.68 (1H, m).

Example 345(R)—N-(5-fluoroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 7-Fluoroisoquinolin-3-amine and 5-fluoroisoquinolin-3-amine

A mixture of methyl 2,2-diethoxyacetimidate (1.5 g, 10.2 mmol) and(3-fluorophenyl)methanamine (1.275 g, 10.2 mmol) in methanol (10 ml) wasstirred for 2 h at 70 degree. The solvent was evaporated to an oil,2,2-diethoxy-N-(3-fluorobenzyl)acetimidamide (2.5 g. 100%). ¹H NMR (500MHz, CDCl3) δ ppm 7.3-6.9 (m, 4H), 4.9 (s, 1H), 4.4 (s, 2H), 3.8-3.5 (m,4H), 1.27-1.20 (q, 6H). MS (LCMS in ammonium acetate system)[M+H]=254.7.

To the above prepared oil (2.1 g) in CH₂Cl₂ (3 ml) at RT was added 2 mlconcentrated sulfuric acid very slowly and then it was stirred at RTovernight. The mixture was poured into ice water and neutralized to pH=8with NaOH (10N). The mixture was extracted with EtOAc (100 ml×3). Theorganic layers were combined and washed with water, brine and dried overNa₂SO₄ to obtain a crude solid, 1.05 g which was used directly withoutfurther purification.

Step B: 5-Fluoro-3-isothiocyanatoisoquinoline

To a solution of the above crude mixture (1050 mg, 6.47 mmol) inmethylene chloride (30 ml) was added1,1′-thiocarbonyldipyridin-2(1H)-one (1500 mg, 6.5 mmol). The pinksolution was stirred for 2 h at RT and then the solvent was evaporatedto obtain a crude red solid which was purified on the Biotage (0-25%ethyl acetate-hexane), isolating the first peak, identified as7-fluoro-3-isothiocyanatoisoquinoline (635 mg, 3.11 mmol, 48%). ¹H NMR(500 MHz, CDCl3) δ ppm 9.08 (s, 1H), 7.9-7.8 (m, 1H), 7.7-7.6 (m, 1H),7.6-7.5 (m, 2H), and the second isomer,5-fluoro-3-isothiocyanatoisoquinoline (27.5 mg, 0.135 mmol, 2.1%). ¹HNMR (500 MHz, CDCl3) δ ppm 9.15 (s, 1H), 7.9-7.8 (m, 1H), 7.7 (s, 1H),7.6-7.5 (m, 1H), 7.5-7.4 (m, 1H).

Step C:(R)—N-(5-Fluoroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To a solution of 5-fluoro-3-isothiocyanatoisoquinoline (27.5 mg, 0.135mmol) in DMF (5 ml) was added (S)-3-(aminomethyl)quinuclidin-3-oldihydrochloride (25 mg, 0.160 mmol) and cesium carbonate (110 mg, 0.337mmol). The mixture was stirred at 40 degree overnight. To the reactionwas then added N,N′-methanediylidenedipropan-2-amine (0.12 g, 0.95 mmol)and the mixture was stirred at 40 degree overnight. The solvent wasevaporated and the crude solid was purified on the Biotage, first in100% ethyl acetate and then 0-25% 9:1 methanol: ammoniumhydroxide-chloroform in a second run to afford(R)—N-(5-fluoroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(29.4 mg, 0.086 mmol, 64.1%).

¹H NMR (500 MHz, MeOD) δ ppm 9.09 (s, 1H), 7.80-7.75 (d, 1H), 7.50-7.30(m, 3H), 4.02-4.00 (d, 1H), 3.70-3.60 (d, 1H), 3.4-3.2 (m, 1H), 3.2-3.1(m, 1H), 3.1-2.9 (m, 2H), 2.9-2.8 (m, 2H), 2.2-2.1 (m, 2H), 1.8-1.6 (m,3H). MS (LCMS) [M+H]=327.08.

Example 346(R)—N-(8-Bromo-5-fluoroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: Methyl 2,2-diethoxyacetimidate

To a solution of sodium methoxide (13.38 g, 248 mmol) in MeOH (300 mL)was added dropwise 2,2-diethoxyacetonitrile (17.22 mL, 124 mmol). Theresulting mixture was stirred at rt for 16 h. The reaction was thendiluted with 300 mL of water and the product was extracted with 3× 250mL of Et₂O. The combined Et₂O layers were washed with 100 mL of brine,dried over sodium sulfate, and evaporated to give the desired product asa colorless liquid (15.3 g, 95 mmol, 77% yield). ¹H NMR (400 MHz, CDCl₃)δ ppm 7.86 (1H, br. s.), 4.77 (1H, s), 3.78 (3H, s), 3.55 (4H, qd,J=6.97, 4.28 Hz), 1.21 (7H, t, J=7.05 Hz).

Step B: (2-Bromo-5-fluorophenyl)methanamine

To a solution of 2-bromo-5-fluorobenzonitrile (3.0 g, 15.00 mmol) andNaBH₄ (1.419 g, 37.5 mmol) in THF (30 mL) was slowly added TFA (3.47 mL,45.0 mmol) over a period of 20 min. The resulting mixture was stirred atrt for 16 hours, then MeOH (10 mL) was added and the mixture was stirredfor another 30 min. It was then diluted with EtOAc (200 mL), washed withwater, dried over Na₂SO₄ and evaporated. The residue was purified on an80 g Thompson silica cartridge (3% to 100% B in Hexanes, 1200 mL, B: 10%MeOH in EtOAc). The desired product was obtained as a colorless oil(1.70 g, 8.33 mmol, 55.5% yield). LC/MS (0.647 min, MH+: 205.92). ¹H NMR(500 MHz, DMSO-d₆) δ ppm 7.59 (1H, dd, J=8.85, 5.49 Hz), 7.43 (1H, dd,J=10.07, 3.05 Hz), 7.05 (1H, td, J=8.47, 3.20 Hz), 3.72 (3H, s), 2.00(2H, br. s.).

Step C: N-(2-bromo-5-fluorobenzyl)-2,2-diethoxyacetimidamide

A mixture of methyl 2,2-diethoxyacetimidate (1.264 g, 7.84 mmol) and(2-bromo-5-fluorophenyl)methanamine (1.6 g, 7.84 mmol) in MeOH (20 mL)was stirred at 75° C. for 2 h. The solvent was evaporated off to providethe crude product as a pale yellow solid.N-(2-bromo-5-fluorobenzyl)-2,2-diethoxyacetimidamide (2.61 g, 7.83 mmol,100% yield) which was used directly in the next step. LC/MS (1.188 min,MH+: 334.92). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.44 (1H, dd, J=8.69, 5.16Hz), 7.15 (1H, dd, J=9.44, 2.90 Hz), 6.81 (1H, td, J=8.25, 3.15 Hz),5.48 (1H, br. s.), 4.90 (1H, s), 4.42 (2H, s), 3.49-3.67 (4H, m),1.17-1.25 (6H, m).

Step D: 8-bromo-5-fluoroisoquinolin-3-amine

To a mixture of N-(2-bromo-5-fluorobenzyl)-2,2-diethoxyacetimidamide(1.6 g, 4.80 mmol) and dichloromethane (2 mL) was added H₂SO₄ (1.280 mL,24.01 mmol). The reaction mixture was stirred at 80° C. for 16 hours,cooled to rt., diluted with EtOAc (100 mL), quenched with ice-water, andneutralized with NaHCO₃ solution. The organic phase was washed withwater, dried over Na₂SO₄, and evaporated. The residue was purified on an80 g Thompson silica cartridge (3% to 100% EtOAc in Hexanes, 1200 mL).The desired product was obtained as a pale yellow solid (0.47 g, 1.950mmol, 40.6% yield).

LC/MS (1.052 min, MH+: 242.99). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.95(1H, s), 7.36 (1H, dd, J=8.06, 4.53 Hz), 7.23 (1H, dd, J=10.58, 8.06Hz), 6.68 (1H, s), 6.52 (2H, s), ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm−126.83 (1F, s).

Step E: 8-bromo-5fluoro-3-isothiocyanatoisoquinoline

To a mixture of 8-bromo-5-fluoroisoquinolin-3-amine (0.30 g, 1.245 mmol)and dichloromethane (5 mL) was added1,1′-thiocarbonyldipyridin-2(1H)-one (0.318 g, 1.369 mmol). Theresulting mixture was stirred at rt for 3 hours. The product wasdirectly purified on a 40 g Thompson silica cartridge (3% to 100% EtOAcin Hexanes, 1200 mL). The desired product was obtained as a off-whitesolid (0.23 g, 0.812 mmol, 65.3% yield). LC/MS (2.098 min, MH+: 284.93).¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.38 (1H, s), 8.04 (1H, dd, J=8.31, 4.78Hz), 7.96 (1H, s), 7.67 (1H, dd, J=9.82, 8.31 Hz). ¹⁹F NMR (376 MHz,DMSO-d₆) δ ppm −122.13 (1F, s).

Step F:(R)—N-(8-bromo-5-fluoroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

To a mixture of 8-bromo-5-fluoro-3-isothiocyanatoisoquinoline (0.22 g,0.777 mmol) and (S)-3-(aminomethyl)quinuclidin-3-ol, 2 HCl (0.196 g,0.855 mmol) in DMF (5 mL) was added Cs₂CO₃ (0.633 g, 1.943 mmol). Theresulting mixture was stirred at 40° C. for 16 hours.N,N′-methanediylidenedipropan-2-amine (0.294 g, 2.328 mmol) was addedand the stirring was continued at 40° C. for another 16 hours. Thesolvent was evaporated. The product was directly purified on 40 gThompson silica cartridge (3% to 100% B in hexanes, 1500 mL. B: 20% MeOHin EtOAc). The product was further recrystallized from EtOAc. Thedesired product was obtained as a off-white solid (0.11 g, 0.261 mmol,33.6% yield). LC/MS (0.997 min, MH+: 406.98). ¹H NMR (400 MHz, MeOD) δppm 9.30 (1H, s), 7.60 (1H, dd, J=8.18, 4.66 Hz), 7.22 (1H, dd, J=10.07,8.06 Hz), 4.00 (1H, d, J=10.07 Hz), 3.69 (1H, d, J=10.07 Hz), 3.23 (1H,d, J=15.36 Hz), 3.07-3.13 (1H, m), 2.90-2.96 (2H, m), 2.76-2.85 (2H, m),2.15 (2H, br. s.), 1.69-1.81 (2H, m), 1.58-1.67 (1H, m). ¹⁹F NMR (376MHz, MeOD) δ ppm −126.72 (1F, s).

Example 347(R)—N-(6-(1H-imidazol-1-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 4-Chloro-6-(1H-imidazol-1-yl)pyrimidine

A mixture of 4,6-dichloropyrimidine (5.96 g, 40 mmol), imidazole (2.72g, 40.0 mmol), and potassium carbonate (5.53 g, 40.0 mmol) was stirredin DMF (50 mL) at room temperature for 18 h. The reaction was dilutedinto 500 mL water and extracted five times with 150 mL EtOAc. Thecombined organic layers were concentrated and purified by flashchromatography on a 240 g silica gel cartridge with 0 to 10% methanol inethyl acetate to yield 4-chloro-6-(1H-imidazol-1-yl)pyrimidine (4.56 g,63% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.85 (1H, d, J=0.76Hz), 8.45 (1H, s), 7.62 (1H, t, J=1.51 Hz), 7.34 (1H, d, J=0.76 Hz),7.23 (1H, dd, J=1.38, 0.88 Hz). LCMS: RT=0.47 min, MH+=181.1.

Step B: 6-(1H-Imidazol-1-yl)pyrimidin-4-amine

4-Chloro-6-(1H-imidazol-1-yl)pyrimidine (4.0 g, 22.1 mmol) was splitinto two equal portions and separately placed into two sealed tubes witha solution of 7 N ammonia in methanol (40 mL). The tubes were sealed andheated at 65° C. for 20 h, then allowed to stand at room temperature for3 days. The reactions were combined, concentrated and purified by flashchromatography on a 240 g silica gel cartridge with 40 to 100% EtOAc inhexane, then 0 to 50% MeOH in EtOAc to yield6-(1H-imidazol-1-yl)pyrimidin-4-amine (1.43 g, 40%). LCMS: RT=0.39 min,MH+=162.1.

Step C: Dimethyl 6-(1H-imidazol-1-yl)pyrimidin-4-ylcarbonimidodithioate

To a solution of 6-(1H-imidazol-1-yl)pyrimidin-4-amine (1.0 g, 6.2 mmol)in DMF (18 mL) was added 10 M NaOH (1.24 mL, 12.4 mmol) dropwise, carbondisulfide (0.93 mL, 16 mmol), NaOH (1.24 mL, 12.4 mmol), and iodomethane(0.97 mL, 16 mmol) at 15 min intervals. Stirring was continued for 2 h,then the mixture was poured into water. The cloudy solution waspartitioned into EtOAc, washed with water, concentrated, and purified byflash chromatography on a 110 g silica gel cartridge with 10 to 50%EtOAc in hexane to yield dimethyl6-(1H-imidazol-1-yl)pyrimidin-4-ylcarbonimidodithioate (411 mg, 25%yield). ¹H NMR (400 MHz, MeOD) δ ppm 8.79 (1H, d, J=1.01 Hz), 8.65 (1H,d, J=1.01 Hz), 7.96 (1H, t, J=1.51 Hz), 7.33 (1H, d, J=1.01 Hz),7.12-7.19 (1H, m), 2.58 (6H, s). LCMS: RT=0.63 min, MH+=266.1.

Step D:(R)—N-(6-(1H-Imidazol-1-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

A suspension of (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (419mg, 1.8 mmol), dimethyl6-(1H-imidazol-1-yl)pyrimidin-4-ylcarbonimidodithioate (404 mg, 1.5mmol), and cesium carbonate (1.24 g, 3.8 mmol) was stirred in DMF (3.8mL) at 75° C. for 2 h. The reaction was concentrated and purified byflash chromatography on a 40 g silica gel cartridge with 0 to 3% [9:1MeOH/NH4OH] in CHCl₃ to yield(R)—N-(6-(1H-imidazol-1-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(417 mg, 83% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.40 (1H, br.s.), 8.60 (1H, d, J=1.01 Hz), 8.37 (1H, t, J=1.01 Hz), 7.55 (1H, t,J=1.39 Hz), 7.16 (1H, dd, J=1.39, 0.88 Hz), 6.84 (1H, br. s.), 3.98 (1H,d, J=9.57 Hz), 3.64 (1H, d, J=9.57 Hz), 3.34 (1H, dd, J=14.98, 1.64 Hz),2.69-3.04 (5H, m), 2.08-2.21 (2H, m), 1.67-1.78 (1H, m), 1.43-1.62 (2H,m). LCMS: RT=0.26 min, MH+=326.2.

Example 348(R)—N-(6-(4-Methyl-1H-imidazol-1-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 4-Chloro-6-(4-methyl-1H-imidazol-1-yl)pyrimidine

A mixture of 4,6-dichloropyrimidine (11.92 g, 80 mmol),4-methyl-1H-imidazole (6.57 g, 80 mmol), and cesium carbonate (26.1 g,80 mmol) was stirred in DMF (50 mL) at room temperature for 18 h. Thereaction was diluted into 200 mL water and extracted three times with200 mL EtOAc. The combined organic layers were concentrated and purifiedby flash chromatography on a 300 g silica gel cartridge with 25 to 75%ethyl acetate in hexane to yield a mixture of the two regioisomericproducts. The pooled fractions were concentrated to about 200 mL volumeand cooled to yield 4-chloro-6-(4-methyl-1H-imidazol-1-yl)pyrimidine(5.70 g, 37% yield). The positive identification of the4-methylimidazole regioisomer was accomplished by its NMR NOEproperties. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.80 (1H, d, J=0.50Hz), 8.36 (1H, d, J=1.26 Hz), 7.29-7.31 (1H, m), 7.25 (1H, d, J=1.01Hz), 2.27 (3H, d, J=1.01 Hz). LCMS: RT=0.50 min, MH+=195.1.

Step B: 6-(4-Methyl-1H-imidazol-1-yl)pyrimidin-4-amine

A solution of 4-chloro-6-(4-methyl-1H-imidazol-1-yl)pyrimidine (1.18 g,6.1 mmol) in 2 M ammonia (20 mL, 40.0 mmol)/isopropanol was heated at80° C. in a sealed vial for 18 h. After cooling the solid precipitatewas filtered and dried to give6-(4-methyl-1H-imidazol-1-yl)pyrimidin-4-amine (733 mg, 69.0% yield). 1HNMR (400 MHz, DMSO-d6) δ ppm 8.31 (1H, d, J=1.26 Hz), 8.28 (1H, d,J=0.76 Hz), 7.49 (1H, t, J=1.13 Hz), 7.16 (2H, s), 6.50 (1H, d, J=0.76Hz), 2.15 (3H, d, J=0.76 Hz).

LCMS: RT=0.39 min, MH+=176.1.

Step C: Dimethyl6-(4-methyl-1H-imidazol-1-yl)pyrimidin-4-ylcarbonimidodithioate

To a solution of 6-(4-methyl-1H-imidazol-1-yl)pyrimidin-4-amine (700 mg,4.00 mmol) in DMF (12 mL) was added dropwise 10 M NaOH (0.8 mL, 8 mmol),carbon disulfide (0.60 mL, 10 mmol), NaOH (0.8 mL, 8 mmol), andiodomethane (0.62 mL, 10 mmol) at 15 min intervals. Stirring wascontinued for 2 h, then the mixture was poured into water. The cloudysolution was partitioned with EtOAc, washed with water, concentrated,and purified by flash chromatography on a 110 g silica gel cartridgewith 50 to 100% EtOAc in hexane to yield dimethyl6-(4-methyl-1H-imidazol-1-yl)pyrimidin-4-ylcarbonimidodithioate (438 mg,39% yield). 1H NMR (400 MHz, MeOD) δ ppm 8.76 (1H, d, J=1.01 Hz), 8.55(1H, d, J=1.26 Hz), 7.62-7.66 (1H, m), 7.24 (1H, d, J=1.01 Hz), 2.57(6H, s), 2.24 (3H, d, J=1.01 Hz).

LCMS: RT=0.66 min, MH+=280.1.

Step D:(R)—N-(6-(4-Methyl-1H-imidazol-1-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

A suspension of (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (412mg, 1.80 mmol), dimethyl6-(4-methyl-1H-imidazol-1-yl)pyrimidin-4-ylcarbonimidodithioate (419 mg,1.5 mmol), and cesium carbonate (1.22 g, 3.75 mmol) was stirred in DMF(3.8 mL) at 75° C. for 2 h. The reaction was concentrated and purifiedby flash chromatography on a 40 g silica gel cartridge with a pre-run of1% [95:5 MeOH/NH4OH] in EtOAc, then 1 to 2% [95:5 MeOH/NH4OH] in CHCl3to yield(R)—N-(6-(4-methyl-1H-imidazol-1-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(472 mg, 92% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.40 (1H, br.s.), 8.56 (1H, d, J=1.01 Hz), 8.28 (1H, d, J=1.26 Hz), 7.21 (1H, s),6.76 (1H, br. s.), 3.97 (1H, d, J=9.57 Hz), 3.63 (1H, d, J=9.57 Hz),3.33 (1H, dd, J=14.86, 1.76 Hz), 2.62-3.05 (5H, m), 2.24 (3H, d, J=1.01Hz), 2.03-2.19 (2H, m), 1.65-1.81 (1H, m), 1.39-1.62 (2H, m). LCMS:RT=0.25, 0.46 min, MH+=340.3.

Example 349(R)—N-(6-(4-Chloro-1H-imidazol-1-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 4-Chloro-6-(4-chloro-1H-imidazol-1-yl)pyrimidine

A mixture of 4,6-dichloropyrimidine (1.8 g, 12 mmol),4-chloro-1H-imidazole (1.23 g, 12.00 mmol), and cesium carbonate (3.91g, 12.00 mmol) was stirred in DMF (8 mL) at room temperature for 18 h.The reaction was diluted into water and extracted with EtOAc. Thecombined organic layers were concentrated and purified by flashchromatography on a 120 g silica gel cartridge with 0 to 40% ethylacetate in hexane to yield4-chloro-6-(4-chloro-1H-imidazol-1-yl)pyrimidine (1.41 g, 54.6% yield).The positive identification of the 4-chloroimidazole regioisomer wasaccomplished by its NMR NOE properties. 1H NMR (400 MHz, CHLOROFORM-d) δppm 8.86 (1H, d, J=0.76 Hz), 8.33 (1H, d, J=1.51 Hz), 7.54 (1H, d,J=1.76 Hz), 7.30 (1H, d, J=0.76 Hz). LCMS: RT=0.81 min, MH+=215.1

Step B: 6-(4-Chloro-1H-imidazol-1-yl)pyrimidin-4-amine

A solution of 4-chloro-6-(4-chloro-1H-imidazol-1-yl)pyrimidine (0.99 g,4.60 mmol) in 2 M ammonia (20 mL, 40.0 mmol)/isopropanol was heated at80° C. in a sealed vial for 18 h. After cooling the solid precipitatewas filtered and dried to give6-(4-chloro-1H-imidazol-1-yl)pyrimidin-4-amine (884 mg, 98% yield). 1HNMR (400 MHz, DMSO-d6) δ ppm 8.44 (1H, d, J=1.51 Hz), 8.32 (1H, d,J=0.76 Hz), 7.96 (1H, d, J=1.51 Hz), 7.30 (2H, br. s.), 6.58 (1H, d,J=1.01 Hz). LCMS: RT=0.57 min, MH+=196.1.

Step C: Dimethyl6-(4-chloro-1H-imidazol-1-yl)pyrimidin-4-ylcarbonimidodithioate

To a solution of 6-(4-chloro-1H-imidazol-1-yl)pyrimidin-4-amine (850 mg,4.35 mmol) in DMF (12 mL) was added dropwise 10 M NaOH (0.87 mL, 8.7mmol), carbon disulfide (0.65 mL, 10.9 mmol), NaOH (0.87 mL, 8.7 mmol),and iodomethane (0.68 mL, 10.9 mmol) at 15 min intervals. Stirring wascontinued for 2 h and the mixture was poured into water. The cloudysolution was partitioned into EtOAc, washed with water, concentrated,and purified by flash chromatography on a 110 g silica gel cartridgewith 10 to 40% EtOAc in hexane to yield dimethyl6-(4-chloro-1H-imidazol-1-yl)pyrimidin-4-ylcarbonimidodithioate (558 mg,43% yield). 1H NMR approx. 9:1 mixture of rotamers (400 MHz, MeOD) δ ppm8.80 (0.8H, d, J=0.76 Hz), 8.79 (0.2H, d, J=0.50 Hz), 8.59 (1H, d,J=1.51 Hz), 8.50 (0.1H, d, J=1.26 Hz), 7.97 (0.9H, d, J=1.51 Hz), 7.84(0.1H, d, J=1.51 Hz), 7.32 (0.9H, d, J=0.76 Hz), 2.63 (0.6H, s), 2.58(5.4H, s). LCMS: RT=0.94 min, MH+=300.0.

Step D:(R)—N-(6-(4-Chloro-1H-imidazol-1-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

A suspension of (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (412mg, 1.800 mmol), dimethyl6-(4-chloro-1H-imidazol-1-yl)pyrimidin-4-ylcarbonimidodithioate (450 mg,1.5 mmol), and cesium carbonate (1.22 g, 3.75 mmol) was stirred in DMF(3.8 mL) at 75° C. for 2 h. The reaction was concentrated and purifiedby flash chromatography on a 40 g silica gel cartridge with a pre-run of1% [95:5 MeOH/NH4OH] in EtOAc, then 1 to 2% [95:5 MeOH/NH4OH] in CHCl3to yield(R)—N-(6-(4-chloro-1H-imidazol-1-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(265 mg, 48% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.41 (1H, br.s.), 8.60 (1H, d, J=1.01 Hz), 8.25 (1H, d, J=1.51 Hz), 7.44 (1H, d,J=1.51 Hz), 6.78 (1H, s), 4.00 (1H, d, J=9.82 Hz), 3.67 (1H, d, J=9.57Hz), 3.36 (1H, dd, J=14.86, 1.51 Hz), 2.73-3.06 (5H, m), 2.09-2.22 (2H,m), 1.69-1.79 (1H, m), 1.46-1.64 (2H, m). LCMS: RT=0.54 min, MH+=360.2.

Example 350(R)—N-(6-(1H-Pyrazol-1-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 4-Chloro-6-(1H-pyrazol-1-yl)pyrimidine

A mixture of 4,6-dichloropyrimidine (5.96 g, 40 mmol), 1H-pyrazole (2.72g, 40.0 mmol), and cesium carbonate (13.03 g, 40.0 mmol) was stirred inDMF (25 mL) at room temperature for 18 h. The reaction was diluted into100 mL water and extracted with EtOAc. The combined organic layers wereconcentrated and purified by flash chromatography on a 240 g silica gelcartridge with 0 to 20% ethyl acetate in hexane to yield4-chloro-6-(1H-pyrazol-1-yl)pyrimidine (4.80 g, 66% yield). 1H NMR (400MHz, CHLOROFORM-d) δ ppm 8.77 (1H, d, J=0.76 Hz), 8.55 (1H, d, J=2.77Hz), 7.96 (1H, d, J=1.01 Hz), 7.80 (1H, d, J=1.01 Hz), 6.51 (1H, dd,J=2.64, 1.64 Hz).

LCMS: RT=0.86 min, MH+=181.1

Step B: 6-(1H-Pyrazol-1-yl)pyrimidin-4-amine

A solution of 4-chloro-6-(1H-pyrazol-1-yl)pyrimidine (1.31 g, 7.25 mmol)in 2 M ammonia (20 mL, 40.0 mmol)/isopropanol was heated at 80° C. in asealed vial for 24 h. The reaction was stored at room temperature for 4days. The solid precipitate was filtered and dried to give6-(1H-pyrazol-1-yl)pyrimidin-4-amine (1.15 g, 98% yield). 1H NMR (400MHz, DMSO-d6) δ ppm 8.53 (1H, dd, J=2.52, 0.50 Hz), 8.30 (1H, d, J=0.76Hz), 7.82 (1H, d, J=1.01 Hz), 7.19 (2H, br. s.), 6.88 (1H, d, J=1.01Hz), 6.55 (1H, dd, J=2.64, 1.64 Hz). LCMS: RT=0.52 min, MH+=162.1.

Step C: Dimethyl 6-(1H-pyrazol-1-yl)pyrimidin-4-ylcarbonimidodithioate

To a solution of 6-(1H-pyrazol-1-yl)pyrimidin-4-amine (1.0 g, 6.20 mmol)in DMF (18 mL) was added dropwise 10 M NaOH (1.24 mL, 12.4 mmol), carbondisulfide (0.933 mL, 15.5 mmol), NaOH (1.24 mL, 12.4 mmol), andiodomethane (0.966 mL, 15.5 mmol) at 15 min intervals. Stirring wascontinued overnight and the mixture was poured into water. The tanprecipitate was filtered, washed with water, and dried to yield dimethyl6-(1H-pyrazol-1-yl)pyrimidin-4-ylcarbonimidodithioate (136 mg, 8%yield).

1H NMR (400 MHz, MeOD) δ ppm 8.74 (1H, d, J=1.01 Hz), 8.64 (1H, d,J=2.52 Hz), 7.82 (1H, d, J=1.26 Hz), 7.40 (1H, d, J=1.01 Hz), 6.57 (1H,dd, J=2.64, 1.64 Hz), 2.58 (6H, s). LCMS: RT=0.96 min, MH+=266.1.

Step D:(R)—N-(6-(1H-Pyrazol-1-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

A suspension of (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (135mg, 0.59 mmol), dimethyl6-(1H-pyrazol-1-yl)pyrimidin-4-ylcarbonimidodithioate (130 mg, 0.49mmol), and cesium carbonate (399 mg, 1.23 mmol) was stirred in DMF (1.2mL) at 75° C. for 2 h. The reaction was concentrated and purified byflash chromatography on a 40 g silica gel cartridge with a pre-run of 1%[95:5 MeOH/NH4OH] in EtOAc, then isocratic 1% [95:5 MeOH/NH4OH] in CHCl3to yield(R)—N-(6-(1H-pyrazol-1-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(105 mg, 66% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.46 (1H, br.s.), 8.58 (1H, d, J=1.01 Hz), 8.50 (1H, dd, J=2.64, 0.63 Hz), 7.74 (1H,d, J=1.01 Hz), 7.47 (1H, br. s.), 6.44 (1H, dd, J=2.64, 1.64 Hz), 3.98(1H, d, J=9.57 Hz), 3.65 (1H, d, J=9.57 Hz), 3.39 (1H, dd, J=14.86, 1.51Hz), 2.71-3.09 (5H, m), 2.10-2.26 (2H, m), 1.69-1.80 (1H, m), 1.48-1.64(2H, m). LCMS: RT=0.51 min, MH+=326.2.

Example 351(R)—N-(6-(1H-1,2,4-triazol-1-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

Step A: 4-Chloro-6-(1H-1,2,4-triazol-1-yl)pyrimidine

A mixture of 4,6-dichloropyrimidine (5.96 g, 40 mmol), 1H-1,2,4-triazole(1.381 g, 20.00 mmol), and cesium carbonate (13.03 g, 40.0 mmol) wasstirred in DMF (25 mL) at room temperature for 16 h. The reaction wasdiluted with 100 mL water and extracted with EtOAc. The combined organicextracts were concentrated and purified by flash chromatography on a 160g silica gel cartridge with 25 to 50% EtOAc in hexane to yield4-chloro-6-(1H-1,2,4-triazol-1-yl)pyrimidine (2.78 g, 38% yield). 1H NMR(400 MHz, CHLOROFORM-d) δ ppm 9.21 (1H, s), 8.87 (1H, s), 8.15 (1H, s),7.91 (1H, s). LCMS: RT=0.68 min, MH+=182.1.

Step B: 6-(1H-1,2,4-Triazol-1-yl)pyrimidin-4-amine

A solution of 4-chloro-6-(1H-1,2,4-triazol-1-yl)pyrimidine (1.24 g, 6.83mmol) in 2 M ammonia (20 mL, 40.0 mmol)/isopropanol was heated at 80° C.in a sealed vial for 18 h. After cooling the solid precipitate wasfiltered and dried to give 6-(1H-1,2,4-triazol-1-yl)pyrimidin-4-amine(1.06 g, 96% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.30 (1H, s), 8.35(1H, s), 8.30 (1H, s), 7.39 (2H, br. s.), 6.83 (1H, d, J=0.76 Hz). LCMS:RT=0.41 min, MH+=163.1.

Step C: Dimethyl6-(1H-1,2,4-triazol-1-yl)pyrimidin-4-ylcarbonimidodithioate

To a solution of 6-(1H-1,2,4-triazol-1-yl)pyrimidin-4-amine (1.00 g,6.17 mmol) in DMF (18 mL) was added dropwise 10 M NaOH (1.23 mL, 12.3mmol), carbon disulfide (0.927 mL, 15.4 mmol), NaOH (1.23 mL, 12.3mmol), and iodomethane (0.96 mL, 15 mmol) at 15 min intervals. Stirringwas continued for 2 h and the mixture was poured into water. The cloudysolution was partitioned with EtOAc, washed with water, concentrated,and purified by flash chromatography on a 110 g silica gel cartridgewith 10 to 50% EtOAc in hexane to yield dimethyl6-(1H-1,2,4-triazol-1-yl)pyrimidin-4-ylcarbonimidodithioate (541 mg, 33%yield). 1H NMR 4:1 mixture of rotamers (400 MHz, MeOD) δ ppm 9.42(0.74H, s), 9.40 (0.35H, s), 9.04 (0.32H, s), 8.84 (0.76H, d, J=1.01Hz), 8.81 (0.33H, d, J=1.01 Hz), 8.23 (1H, s), 7.42 (0.75H, d, J=1.01Hz), 2.64 (1.2H, s), 2.59 (4.8H, s). LCMS: RT=0.86 min, MH+=267.1.

Step D:(R)—N-(6-(1H-1,2,4-Triazol-1-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

A suspension of (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (412mg, 1.800 mmol), dimethyl6-(1H-1,2,4-triazol-1-yl)pyrimidin-4-ylcarbonimidodithioate (400 mg, 1.5mmol), and cesium carbonate (1222 mg, 3.75 mmol) was stirred in DMF (3.8mL) at 75° C. for 2 h. The reaction was concentrated and purified byflash chromatography on a 40 g silica gel cartridge with a pre-run of 1%[95:5 MeOH/NH4OH] in EtOAc, then 1 to 3% [95:5 MeOH/NH4OH] in CHCl3 toyield(R)—N-(6-(1H-1,2,4-triazol-1-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine(210 mg, 43% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.45 (1H, br.s.), 9.14 (1H, s), 8.61 (1H, d, J=1.01 Hz), 8.08 (1H, s), 7.39 (1H, s),4.00 (1H, d, J=9.57 Hz), 3.67 (1H, d, J=9.57 Hz), 3.38 (1H, dd, J=14.86,1.76 Hz), 2.71-3.08 (5H, m), 2.08-2.23 (2H, m), 1.68-1.80 (1H, m),1.45-1.64 (2H, m). LCMS: RT=0.46 min, MH+=327.2.

Example 352(S)—N-(Isoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine

(S)—N-(Isoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-aminewas prepared by the method of Example 239 (steps A-B), starting from(R)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride. ¹H NMR (400 MHz,MeOD) δ ppm 9.00 (1H, s), 7.91 (1H, d, J=8.06 Hz), 7.70 (1H, d, J=8.31Hz), 7.58 (1H, t, J=7.18 Hz), 7.40 (1H, t, J=7.05 Hz), 7.30 (1H, br.s.), 3.95 (1H, d, J=9.82 Hz), 3.64 (1H, d, J=10.07 Hz), 3.16-3.25 (1H,m), 3.02-3.13 (1H, m), 2.92 (2H, t, J=7.30 Hz), 2.80 (2H, t, J=7.05 Hz),2.05-2.23 (2H, m), 1.52-1.84 (3H, m). MS (LC/MS) R.T.=1.39;[M+H]⁺=309.21.

It will be evident to one skilled in the art that the present disclosureis not limited to the foregoing illustrative examples, and that it canbe embodied in other specific forms without departing from the essentialattributes thereof. It is therefore desired that the examples beconsidered in all respects as illustrative and not restrictive,reference being made to the appended claims, rather than to theforegoing examples, and all changes which come within the meaning andrange of equivalency of the claims are therefore intended to be embracedtherein.

1. A pharmaceutical composition comprising a therapeutically effectiveamount of(R)—N-(6-(1H-imidazol-1-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 2. A method for the treatment of schizophrenia,Alzheimer's Disease, cognitive disorders, rheumatoid arthritis,osteoarthritis, ulcerative colitis, Crohn's Disease, or diabetescomprising administering a therapeutically affective amount of(R)—N-(6-(1H-imidazol-1-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amineto a patient.
 3. The method of claim 2 directed to schizophrenia.
 4. Themethod of claim 2 directed to Alzheimer's disease.